11,12-Secoprostaglandins

ABSTRACT

This invention relates to 11,12-secoprostaglandins and processes for their manufacture. These compounds have prostaglandin-like biological activity and are particularly useful as renal vasodilators, for the treatment of hypertension, for the prevention of thrombus formation, in preventing gastric secretion, and as regulators of the immune response.

RELATIONSHIP TO OTHER APPLICATIONS

This is a division of application Ser. No. 669,118 filed Mar. 22, 1976;U.S. Pat. No. 4,066,692 which is a continuation-in-part application ofSer. No. 571,038 filed Apr. 23, 1975 filed and now abandoned; which inturn is a continuation-in-part of Ser. No. 389,901 Aug. 23, 1973 and nowabandoned; which in turn is a continuation-in-part of Ser. No. 302,365filed Oct. 30, 1972 and now abandoned.

SUMMARY OF THE INVENTION

This invention relates to novel 11,12-secoprostaglandins which can berepresented by the following formula: ##STR1## wherein R is selectedfrom the group consisting of carboxy and a carboxy salt whichincorporates a pharmaceutically acceptable cation, such as metal cationsderived from alkali metals, alkaline earth metals, and amines such asammonia, primary and secondary amines, and quaternary ammoniumhydroxides. Especially preferred metal cations are those derived fromalkali metals, e.g., sodium, potassium, lithium, and the like, andalkaline earth metals, e.g., calcium, magnesium, and the like and othermetals, i.e., aluminum, iron and zinc.

Pharmaceutically acceptable cations can be formed from primary,secondary, or tertiary amines, or quaternary ammonium hydroxides such asmethylamine, dimethylamine, trimethylamine, ethylamine,N-methylhexylamine, benzylamine, α-phenethylamine, ethylenediamine,piperidine, morpholine, pyrrolidine, 1,4-dimethylpiperazine,ethanolamine, diethanolamine, triethanolamine,tris(hydroxymethyl)aminomethane, N-methylglucamine, N-methylglucosamine,ephedrine, procaine, tetramethylammonium hydroxide, tetraethylammoniumhydroxide, benzyltrimethylammonium and the like.

R is also selected from alkoxycarbonyl (--COOY) where Y is alkyl having1-10 carbon atoms, 1-succinimidoethyl, 1-(pivaloyloxy)ethyl,2-acetamidoethyl or diloweralkylaminoloweralkyl; carbamoyl (--CONH₂);substituted carbamoyl (--CONR⁶ R⁷) wherein R⁶ and R⁷ are selected fromthe group consisting of hydrogen, lower alkyl having 1-4 carbon atomsand diloweralkylaminoalkyl having 4-7 carbon atoms; and carbazoyl(--CONHNH₂).

A is selected from the group consisting of ethylene (--CH₂ CH₂),trimethylene (--CH₂ CH₂ CH₂ --), α-methylethylene (--CH₂ --CH (CH₃)--),β-methylethylene (--CH(CH₃)CH₂ --), α,α-dimethylethylene (--CH₂--C(CH₃)₂ --), β,β-dimethylethylene (--C(CH₃)₂ CH₂ --) and oxymethylene(--O--CH₂ --). (Note that when A consists of a two carbon bridge, theterm "α" refers to the carbon adjacent to R, while "β" refers to theother carbon atom.)

R¹ is selected from the group consisting of formyl, acetyl, propionyl,acryloyl, hydroxyacetyl, 3-hydroxypropionyl, hydroxymethyl,1-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihyroxypropyl, and1-hydroxy-1-methylethyl.

Z is selected from the group consisting of methylene, ethylene,trimethylene, tetramethylene, vinylene (--CH═CH--), and ethynylene(--C.tbd.C--).

R² is independently selected from the group consisting of hydrogen andmethyl.

R³ is selected from the group consisting of hydrogen, and lower alkanoylof 1-5 carbon atoms, e.g., formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, pivaloyl, and the like.

R⁴ is selected independently from the group consisting of hydrogen andmethyl.

R⁵ is selected from the group consisting of hydrogen, lower alkyl of 1-4carbon atoms, either straight or branched (e.g., methyl, ethyl, propyl,isopropyl, butyl, tert-butyl), vinyl, and 2,2,2-trifluoroethyl.

In addition, when R⁵ is lower alkyl and R² is methyl, they can be joinedtogether (with abstraction of hydrogen) to form a carbocyclic ring withfrom 6 to 9 members.

Also, when R⁵ is lower alkyl and R² is hydrogen, R⁵ can be joined to thecarbon atom bearing R² and OR³ to form a carbocyclic ring with from 5 to8 members.

It is to be recognized that the carbon atom marked by an asterisk (*)and, in some instances, the carbon atoms marked by a dagger are chiral.In addition, certain carbon atoms included in R⁵ are also chiral. Thecompounds of this invention are understood to include the individualstereoisomers and mixtures of stereoisomers, the biological activity ofwhich will vary but which may readily be determined in the in vitro andin vivo assays described hereinbelow.

A preferred embodiment of this invention relates to the11,12-secoprostaglandins having the following general formula: ##STR2##wherein A' is ethylene or oxymethylene; R⁸ is acetyl, propionyl,1-hydroxyethyl or 1-hydroxy-1-methylethyl; R², R³, and R⁴ are as definedabove and R⁹ is lower alkyl of 1-4 carbon atoms. In addition, when R² ismethyl, R⁹ and R² can be joined together to form a carbocyclic ring withfrom 6 to 9 members. Also, when R² is hydrogen, R⁹ can be joined to thecarbon bearing R² and OR³ to form a carbocyclic ring with from 5 to 8members.

BACKGROUND OF THE INVENTION

The compounds of Formula I are described as 11,12-secoprostaglandinsbecause of their structural relationship to the naturally-occurringprostaglandins.

The prostaglandins constitute a biologically prominent class ofnaturally-occurring, highly-functionalized C₂₀ fatty acids which areanabolized readily in a diverse array of mammalian tissues from threeessential fatty acids; namely, 8,11,14-eicosatrienoic acid,5,8,11,14-eicosatetraenoic acid, and 5,8,11,14,17-eicosapentaenoic acid.Each known prostaglandin is a formal derivative of the parent compound,termed "prostanoic acid"; the latter is a C₂₀ fatty acid covalentlybridged between carbons 8 and 12 such as to form a trans,vicinally-substituted cyclopentane in which the carboxy-bearing sidechain is "alpha" or below the plane of the ring, and the other sidechain is "beta" or above the plane of the ring as depicted in formulaIII: ##STR3##

Prostaglandins have been shown to occur extensively in lowconcentrations in a myriad of mammalian tissues where they are bothrapidly anabolized and catabolized and to exhibit a vast spectrum ofpharmacological activities including prominent roles in (a) functionalhyperemia, (b) the inflammatory response, (c) the central nervoussystem, (d) transport of water and electrolytes, and (e) regulation ofcyclic AMP. Further details concerning the prostaglandins can be foundin recent reviews of their chemistry [J. E. Pike, Fortschr. Chem. Org.Naturst., 28, 313 (1970) and G. F. Bundy, A. Rep. in Med. Chem., 7, 157(1972)]; biochemistry [J. W. Hinman, A. Rev. Biochem., 41, 161 (1972)];pharmacology [J. R. Weeks, A. Rev. Pharm., 12, 317 (1972)];physiological significance [E. W. Horton, Physiol. Rev., 49, 122(1969)]; and general clinical application [J. W. Hinman, Postgrad. Med.J., 46, 562 (1970)].

The potential application of natural prostaglandins as medicinallyuseful therapeutic agents in various mammalian disease states is obviousbut suffers from three formidable major disadvantages, namely, (a)prostaglandins are known to be rapidly metabolized in vivo in variousmammalian tissues to a variety of metabolites which are devoid of thedesired original biological activities, (b) the natural prostaglandinsare inherently devoid of biological specificity which is requisite for asuccessful drug, and (c) although limited quantities of prostaglandinsare presently produced by both chemical and biochemical processes, theirproduction cost is extremely high; and consequently, their availabilityis quite restricted.

Our interest has, therefore, been to synthesize novel compoundsstructurally related to the natural prostaglandins, but with thefollowing unique advantages: (a) simplicity of synthesis leading to lowcost of production; (b) specificity of biological activity which may beeither of a prostaglandin-mimicking or prostaglandin-antagonizing type;(c) enhanced metabolic stability. The combination of these advantagesserves to provide effective, orally and parenterally active therapeuticagents for the treatment of a variety of human and animal diseases.Included are applications in renal, cardiovascular, gastrointestinal,respiratory, and reproductive systems, and in the control of lipidmetabolism, inflammation, blood clotting, skin diseases, growth hormonerelease, selected cancers, and certain autoimmune diseases.

The compounds of the present invention are useful as pharmaceuticallyactive compounds. Thus, these compounds are orally active in thetreatment of conditions which are responsive to the actions of thenatural prostaglandins. It is, of course, necessary to determine byroutine laboratory testing which of the compounds of the presentinvention are most suitable for a specific end use. Some of thecompounds of the invention have prostaglandin-like activity in that theymimic the effect of prostaglandin E₁ in stimulating the formulation ofcyclic AMP in the mouse ovary in vitro.

Examples of compounds which are useful in stimulating the formation ofcyclic AMP in the mouse ovary are:

(a) 8-acetyl-12-hydroxyheptadecanoic acid

(b) 8-acetyl-13-hydroxyheptadecanoic acid

(c) 8-acetyl-14-hydroxyheptadecanoic acid

(d) 8-acetyl-11-hydroxyheptadecanoic acid

(e) 8-acetyl-12-hydroxy-(E)-10-heptadecenoic acid

(f) 8-propionyl-12-hydroxyheptadecanoic acid

(g) 8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid

(h) 8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid

(i) 8-hydroxymethyl-12-hydroxyheptadecanoic acid

(j) 8-acetyl-12-hydroxy-16-methylheptadecanoic acid

(k) 8-acetyl-12-hydroxynonadecanoic acid

(l) 8-(1,3-dihydroxypropyl)-12-hydroxyheptadecanoic acid

(m) 9-acetyl-12-hydroxyheptadecanoic acid

(n) 8-acetyl-12-acetoxyheptadecanoic acid

(o) (5-acetyl-9-hydroxytetradecyloxy)acetic acid

(p) methyl 8-acetyl-12-hydroxyheptadecanoate

(q) 8-glycoloyl-12-hydroxyheptadecanoic acid

(r) 8-acetyl-12-hydroxy-13,13-dimethylheptadecanoic acid

(s) 8-acetyl-12-hydroxy-10-heptadecynoic acid

(t) 8-(1-hydroxy-1-methylethyl)-12-hydroxy-12-methylheptadecanoic acid

(u) 8-acetyl-11-(1-hydroxycyclohexyl)-10-undecynoic acid

(v) 8-(1-hydroxyethyl)-12-hydroxy-(E)-10-heptadecenoic acid

(w) 8-(1-hydroxyethyl)-12-hydroxy-12-methylheptadecanoic acid

Certain of the compounds of the invention which do not mimic the effectof prostaglandin E₁ are active as antagonists of prostaglandin E₁ incertain smooth muscle tissues, such as intestinal and uterine tissue.Such components would be useful in the prevention of abortion and in thetreatment of diarrhea.

An example of the compounds of our invention active in antagonizing theeffect of prostaglandin E₁ in uterus and intestinal tissue are compoundswhich have additional methyl substituents in the alpha position relativeto the carboxy group, as for example,2-methyl-8-acetyl-12-hydroxyheptadecanoic acid.

In addition, certain of the compounds of the present invention mimic theeffects of prostaglandin E₁ in producing renal vasodilation inlaboratory animals. Thus, they can be used to improve renal function inanimals with poorly-functioning kidneys. Examples of such compounds are:

(a) 8-acetyl-12-hydroxyheptadecanoic acid

(b) 8-acetyl-13-hydroxyheptadecanoic acid

(c) 8-acetyl-14-hydroxyheptadecanoic acid

(d) 8-acetyl-11-hydroxyheptadecanoic acid

(e) 8-acetyl-12-hydroxy-(E)-10-heptadecenoic acid

(f) 8-propionyl-12-hydroxyheptadecanoic acid

(g) 8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid

(h) 8-hydroxymethyl-12-hydroxyheptadecanoic acid

(i) 8-acetyl-12-hydroxynonadecanoic acid

(j) 8-acetyl-12-acetoxyheptadecanoic acid

(k) (5-acetyl-9-hydroxytetradecyloxy)acetic acid

(l) 8-acetyl-12-hydroxy-13,13-dimethylheptadecanoic acid

(m) 8-acetyl-11-(1-hydroxycyclohexyl)undecanoic acid

Also, certain of the compounds of this invention have antihypertensiveactivity as shown by the fact that they lower blood pressure in a strainof laboratory rats which have blood pressure higher than that observedin normal rats, and thus are useful in the treatment of hypertension. Anexample of such a compound is 8-acetyl-12-hydroxyheptadecanoic acid.

In addition, certain of the compounds of this invention are effective ininhibiting the aggregation of platelets in blood stimulated withcollagen to cause platelet aggregation. Thus, in inhibiting plateletaggregation, they are useful in preventing thrombus formation. Examplesof compounds of this type are:

(a) 8-acetyl-12-hydroxyheptadecanoic acid

(b) 8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid

(c) (5-acetyl-9-hydroxytetradecyloxy)acetic acid

Also, certain of the compounds of our invention, for example8-acetyl-12-hydroxyheptadecanoic acid, may have utility as antiulceragents in that they are active in inhibiting gastric secretion inlaboratory animals. In one test used to establish this activity, dogswith a chronic gastric fistula are treated with pentagastrin, asubstance which ordinarily evokes secretion in such animals. Activity inthe test compound is shown when the secretion caused by the testcompound is inhibited to some degree.

The compounds of this invention are also indicated to be useful intherapy as regulators of the immune response. The basis for theiractivity in this area is their ability to stimulate cyclic-AMP formationin cells. Agents, including the E prostaglandins, that increase cellularcyclic-AMP concentration, interfere with the cell-mediated immuneresponse by inhibiting lymphocyte expression in response to antigen, byinhibiting release of pathological mediators from sensitizedlymphocytes, and by inhibiting the killing of target cells by suchlymphocytes. Various assays which depend upon the measurement of somefunction of the immunologically competent lymphocyte can be used todemonstrate that the prostaglandin analogs of this invention aresimilarly active. For example, the release of lymphokines (proteins thatare agents of inflammation and tissue destruction) from sensitizedlymphocytes in culture is strongly inhibited by these analogs in lowconcentrations. Thus, it is apparent that the compounds of thisinvention are applicable to the treatment of those autoimmune diseasesin whose pathogenesis a cell-mediated immune reaction is involved. Suchdiseases range from contact dermatitis to such chronic destructivediseases as rheumatoid arthritis and possibly multiple sclerosis andsystemic lupus erythematosus.

The present prostaglandin analogs are also effective in preventing therejection of transplanted organs. The biochemical basis for this actionis the same as outlined in the preceding paragraph, for the rejection oforgan grafts is considered to be predominantly a cell-mediated immunephenomenon and the hallmark of organ rejection is the infiltration ofcytotoxic lymphocytes into the graft. Direct evidence that the compoundsof this invention can retard or prevent transplant rejection has beenobtained in the rat renal allograft model; in this system,administration of the compounds of the present invention prevents therejection of the transplanted kidney and the subsequent death of thehost rat, which events invariably occur in the cases of untreated ratsor those treated with immunosuppressants. An example of a compound whichis an effective regulator of immune responses of the types describedabove is 8-acetyl-12-hydroxyheptadecanoic acid.

Because of their biological activity and ready accessibility, thecompounds of the invention are also useful in that they permit largescale animal testing useful and necessary to understanding of thesevarious disease conditions such as dwarfism caused by poorly-functioningpituitary glands, stroke (thrombus formation), and the like. It will beappreciated that not all of the compounds of this invention have thesebiological activities to the same degree but the choice of anyparticular ones for any given purpose will depend upon several factorsincluding the disease state to be treated.

The compounds of this invention can be administered either topically orsystemically, i.e., intravenously, subcutaneously, intramuscularly,orally, rectally, or by aerosolization in the form of sterile implantsfor long action. They can be formulated in any of a number ofpharmaceutical compositions and non-toxic carriers to this end.

The pharmaceutical compositions can be sterile, injectable suspensionsor solutions, or solid orally-administrable, pharmaceutically-acceptabletablets or capsules; the compositions can also be intended forsublingual administration, or for suppository use. It is especiallyadvantageous to formulate compositions in dosage unit forms for ease andeconomy of administration and uniformity of dosage. "Dosage unit form"as a term used herein refers to physically discrete units suitable asunitary dosages for animal and human subjects, each unit containing apredetermined quantity of active material calculated to produce thedesired biological effect in association with the requiredpharmaceutical means.

Illustratively, a sterile injectable composition can be in the form ofaqueous or oleagenous suspensions or solutions.

The sterile injectable composition can be aqueous or oleagenoussuspension or solution. Suspensions can be formulated according to theknown art using suitable dispersing and wetting agents and suspendingagents. Solutions are similarly prepared from the salt form of thecompound. For the laboratory animals, we prefer to use incompleteFreund's adjuvant or sterile saline (9%) as carrier. For humanparenteral use, such as intramuscularly, intravenously, or by regionalperfusion, the diluent can be a sterile aqueous vehicle containing apreservative; for example, methylparaben, propylparaben, phenol, andchlorobutanol. The aqueous vehicle can also contain sodium chloride,preferably in an amount to be isotonic; as well as a suspending agent,for example, gum arabic, polyvinyl pyrrolidone, methyl cellulose,acetylated monoglyceride (available commercially as Myvacet fromDistillation Products Industry, a division of Eastman Kodak Company),monomethyl glyceride, dimethyl glyceride or a moderately high molecularweight polysorbitan (commercially available under the tradenames Tweenor Span from Atlas Powder Company, Wilmington, Delaware). Othermaterials employed in the preparation of chemotherapeutic compositionscontaining the compound may include glutathione, 1,2-propanediol,glycerol and glucose. Additionally, the pH of the composition isadjusted by use of an aqueous solution such astris(hydroxymethyl)aminomethane (tris buffer).

Oily pharmaceutical carriers can also be used, since they dissolve thecompound and permit high doses. Many oily carriers are commonly employedin pharmaceutical use, such as, for example, mineral oil, lard,cottonseed oil, peanut oil, sesame oil, or the like.

It is preferred to prepare the compositions, whether aqueous or oils, ina concentration in the range of from 2-50 mg./ml. Lower concentrationsrequire needless qualities of liquid. Higher concentrations than 50mg./mg. are difficult to maintain and are preferably avoided.

Oral administration forms of the drug can also be prepared forlaboratory animals or human patients provided that they are encapsulatedfor delivery in the gut. The drug is subject to enzymatic breakdown inthe acid environment of the stomach. The same dosage levels can be usedas for injectable forms; however, even higher levels can be used tocompensate for biodegradation in the transport. Generally, a solid unitdosage form can be prepared containing from 0.5 mg. to 25 mg. activeingredient.

Whatever the mode of administration, doses in the range of about 0.10 to20 milligrams per kilogram of body weight administered one to four timesper day are used. The exact dose depending on the age, weight andcondition of the patient, and the frequency and route of administration.

The low cost and ready accessibility of the compounds of this inventionmake them particularly promising for applications in veterinary medicinein which field their utilities are comparable to those in humanmedicine.

In preparing the new chemical compounds with which this invention isconcerned, we have found it desirable to use as starting materialscompounds which are readily available commercially in any desiredamounts.

There are a number of inter-related processes useful in preparing thecompounds of Formula I. These can all be described as the sub-synthesisof each of the three main moieties of the molecule (i.e., the (CH₂)₄ A-Rchain, the ##STR4## chain; and the R' group; all attached to theasymmetric carbon atom ##STR5## and then their reaction(s) to form thedesired end product. Although not all compounds can be prepared by eachprocess, there is much overlapping so that many compounds can beprepared by one, two, or three of these processes. Certain variantprocesses are involved and each variant of the main processes will bediscussed in relation to the specific compound or compounds produced.

ACETOACETIC ACID PROCESS

One major process which can be used to prepare the compounds of thisinvention is the "acetoacetic ester process".

This is used to yield compounds of formula I when R' is acetyl or(following optional variant procedures) 1-hydroxyethyl and1-hydroxy-1-methylethyl, and R, A, Z, R², R³, R⁴, and R⁵ are as definedin formula I.

The starting material is a lower alkyl ester of acetoacetic acid,##STR6## wherein R¹⁰ is a lower alkyl group having 1-5 carbon atoms andis preferably tert-butyl. However, when reagents VII B or VII C areemployed, as discussed infra, to prepare compounds of formula I whereinZ is vinylene or ethynylene, R¹⁰ must be methyl or ethyl.

The starting compound IV is then treated with an equivalent of base suchas sodium hydride, sodium ethoxide, sodium amide, or the like. Theenolate anion thus produced is alkylated with a compound of the formula:

    X--(CH.sub.2).sub.4 ACOOR.sup.11                           V

wherein X is a halogen atom, preferably bromine or chlorine, A is asdefined in formula I, and R¹¹ is lower alkyl having 1-5 carbon atoms,preferably ethyl. The reaction of the anion from IV with V is conductedin an inert solvent or solvent system such as dimethylformamide,dimethylformamide-benzene (1:1) or diglyme, at a temperature rangingfrom 40° to 120° C. The reactants are employed in approximatelyequimolar amounts. The reaction is complete in 2-4 hours. After IV and Vhave reacted, the intermediate compound ##STR7## is isolated.

Compound VI can then be treated with an equimolar amount of base such asNaH, NaOC₂ H₅, or NaNH₂ and then alkylated with any one of the followingreagents VII A, VII B, VII C or VII D: ##STR8## wherein X is halogen,preferably chlorine or bromine, Z' is methylene, ethylene, trimethylene,and tetramethylene, R⁴ and R⁵ are as defined for formula I, R¹² ishydrogen, lower alkyl of 1-4 carbon atoms, straight or branched, and2,2,2-trifluoroethyl. In intermediates VII C, when R¹² is lower alkyland R² is methyl, they can be joined together to form a carbocyclic ringwith from 6 to 9 members. Also in VII C, when R¹² is lower alkyl and R²is hydrogen, R¹² can be joined to the carbon atom bearing R² to form acarbocyclic ring with from 5 to 8 members.

Whichever of the four reagents VII are employed, the reactant compoundsare employed in approximately equimolar amounts. A solvent is employedsuch as dimethylformamide, dimethylformamide-benzene (1:1), or diglyme.The temperature of the reaction is between 60° and 120° C. The reactionis completed within 12-72 hours.

The various intermediate products obtained, that is, ##STR9## are thenfurther treated as follows to yield the final product I.

For instance, compound VIII A in which R¹⁰ is tert-butyl, is heated insolution (preferably higher boiling inert solvents are used, i.e.,toluene or xylenes) with a trace of acid to effect elimination anddecarboxylation. This process yields the intermediate compound IX:##STR10## which is submitted to mild basic hydrolysis (preferably adilute solution of NaOH in aqueous methanol or ethanol) to yieldcompounds of formula I.

Further, compound VIII A in which R¹⁰ is a primary or secondary loweralkyl group (e.g., methyl, ethyl, or butyl) can be subjected to basichydrolysis to effect cleavage of the ester linkages and decarboxylationand to obtain compounds of formula I, i.e., X: ##STR11##

The compound VIII B (in which R¹⁰ must be a primary or secondary loweralkyl group, i.e., methyl, ethyl, or butyl), is submitted to basichydrolytic conditions to effect hydrolysis and decarboxylation andobtain compounds of formula I, i.e., XI: ##STR12##

The compound VIII C (in which R¹⁰ must be a primary or secondary loweralkyl group, i.e., methyl, ethyl, or butyl) is submitted to basichydrolytic conditions to effect hydrolysis and decarboxylation andobtain compounds of formula I, i.e., XII: ##STR13##

Catalytic hydrogenation of compounds XII produces compounds of formulaI, i.e., XIII: ##STR14##

In the case of compound VIII D, if R¹⁰ is tert-butyl, the compound isfirst heated in an inert solvent with a trace of acid to effectelimination and decarboxylation and obtain compound XIV: ##STR15##

The compound XIV is hydrated by the oxymercuration-demercuration processin which XIV is treated with mercuric acetate in aqueous tetrahydrofuranfor a prolonged period to effect oxymercuration followed by treatment ofthe reaction mixture with sodium borohydride to effect demercuration.The product of this process is compound XV: ##STR16##

Mild basic hydrolysis (NaOH in aqueous methanol or ethanol) of the esterfunction of compound XV yields compounds of formula I, i.e., XVI:##STR17##

In the case of compound VIII D, if R¹⁰ is a primary or secondary alkylgroup, the compound is first subjected to basic hydrolysis to cleaveester linkages and effect decarboxylation and yield compound XVII:##STR18##

The compound XVII is hydrated by the oxymercuration-demercurationprocess described above to yield compounds of formula I, i.e., XVI.

It should be pointed out that the exact order of reacting compound IVwith compound V or any of compounds VII is not critical; either V or VIIcan be the first reactant. Subsequently, the other of the reactants isreacted with the recovered intermediate. The order described above isour preferred route, however.

MALONIC ESTER PROCESS

Another major route useful in preparing compounds of this invention isthe Malonic Ester Process. This process is used to prepare a sub-group(formula XVIII) of compounds of formula I wherein ##STR19## R¹³ ispropionyl, formyl, hydroxyacetyl, or hydroxymethyl, or followingsubsequent reactions, where R¹³ is 1-hydroxyethyl or 1,2-dihydroxyethyl;and R, A, Z', R², R³, R⁴, and R⁵ are as defined previously.

This process utilizes as starting material di-tert-butyl malonate.

This ester is alkylated first with compound V and then with either ofcompounds VII A or VII D. The basic reagents used and the reactionconditions for these alkylations are essentially the same as in thealkylations described in the acetoacetic ester process. At this point,the compounds XIX and XX are obtained: ##STR20##

Either of these compounds is heated in an inert solvent with a trace ofacid to effect elimination of isobutylene and decarboxylation. CompoundsXXI and XXII are obtained, respectively: ##STR21##

In turn, either of these compounds is heated with thionyl chloride at60° to 120° C. for 2 to 6 hours in an inert solvent (e.g., benzene,toluene) to yield the acid chloride intermediates XXIII and XXIV:##STR22##

The compounds XXIII and XXIV are key intermediates in that a variety ofR¹³ groups can be introduced by the reaction of reagents with thechlorocarbonyl functional group. (1) To prepare compounds where R¹³ ispropionyl, intermediates XXIII and XXIV are made to react withdiethylcadmium. (2) To prepare compounds where R¹³ is hydroxymethyl, thechlorocarbonyl function is reduced with sodium borohydride in a suitablenon-protic solvent such as diglyme. (3) To prepare compounds where R¹³is formyl, the chlorocarbonyl function is reduced with lithiumtri-tert-butoxyaluminum hydride. (4) To prepare compounds where R¹³ ishydroxyacetyl, the intermediate XXIII or XXIV is treated withdiazomethane in ether to obtain the diazomethyl ketone which on acidhydrolysis (2N H₂ SO₄ in dioxane, preferably) gives thehydroxyacetyl-substituted compound.

When any of these derivatives are prepared from XXIV, a hydration stepis needed in which the elements of water are added across the doublebond. This is effected by the oxymercuration-demercuration processdescribed previously.

A final step in the preparation of the compounds of this invention isbasic hydrolysis (sodium hydroxide, preferably, in methanol and ethanol)to hydrolyze the protecting ester functions and obtain compounds offormula I, i.e., XXV: ##STR23##

It is frequently advantageous from a therapeutic standpoint to preparecompounds of this invention (formula I) in which the asymmetric carbonatom which bears R² and OR³ is exclusively in the R or S configuration.The compounds of the instant invention, in which the C₁₂ carbon is inthe S-configuration, have greated biological activity than those inwhich the C₁₂ -carbon is in the R-configuration. The relative biopotencyof either isomer is readily determined in any particular instance by useof the in vitro or in vivo assays referred to hereinabove.

In our series of 11,12-secoprostaglandins, compounds exclusively R or Sat this center can be produced by employing in the acetoacetic ormalonic processes, intermediates VII A or VII B which are opticallyactive, i.e., resolved into their R and S isomeric forms.

We have found it particularly advantageous to employ an optically activereagent VII E: ##STR24## in which R² and R¹² are as defined previouslyand the carbon atom marked with an asterisk is exclusively in either theR or S configuration.

The use of VII E in the acetoacetic ester process gives intermediatesVIII E: ##STR25## in which R¹⁰ must be a primary or secondary loweralkyl group, i.e., ethyl or methyl.

Basic hydrolysis of intermediates VIIIE accompanied by decarboxylationgive products of formula I, i.e., XII A, in which the carbon bearing R²and OH ##STR26## is exclusively in the R or S configuration.

Catalytic hydrogenation of products XII a gives compounds of formula I,i.e., XIII a in which ##STR27## the carbon atom bearing R² and OH islikewise exclusively in either the R or S configuration.

THE WITTIG ROUTE

A third, major process for preparing compounds of this invention istermed the "Wittig route" since a key step therein involves thecondensation of a triphenyl phosphorane with a ketone. This processpermits the preparation of compounds of formula I in which Z isethylene, R² and R³ are hydrogen and R, A, R¹, R⁴, and R⁵ are defined asin formula I except when R¹ is hydroxyacetyl or 1,2-dihydroxyethyl.

The starting materials for this process are acid halides of thefollowing formula: ##STR28## wherein R¹¹ is a lower alkyl group having1-5 carbon atoms, preferably methyl or ethyl, and X is a halogen,preferably chloro.

Compounds of formula XXVI are allowed to react with the anions derivedfrom a lower alkyl ester of acetoacetic acid, ##STR29## wherein R¹¹ is alower alkyl group having 1-5 carbon atoms, preferably methyl or ethyl;said anions are generated from reagents of type IV A via treatment witha strong base such as sodium hydride, sodium ethoxide, sodium amide orthe like. This process is effected in an inert solvent, preferablybenzene, toluene or the like, at a temperature of 0° to 25° for a periodranging from 2 to 24 hours and affords substitution products of formulaXXVII: ##STR30## Treatment of compounds XXVII with an alkali metalalkoxide, preferably sodium methoxide, in an alcoholic medium,preferably methanol, at a temperature of about 0° to 25° for a period of2 to 24 hours yields a β-keto ester of formula XXVIII: ##STR31##

Reagents of formula XXVIII are converted to their anions with anequivalent of a strong base such as sodium hydride, sodium amide, sodiummethoxide or the like, and allowed to react in an inert solvent,preferably benzene, benzene-dimethylformamide (1:1) or the like, at atemperature ranging from 25° to 120° for a period of 48 to 120 hours andin the presence of a catalyst, preferably sodium iodide, with compoundsof the following formula: ##STR32## where X═halogen, preferably chlorineor bromine and Z" is ethylene.

The above process provides compounds of formula XXX: ##STR33##

Treatment of compounds XXX with dilute aqueous alkali at a temperatureranging from 0° to 40° for a period of 12 to 74 hours followed byacidification and subsequent decarboxylation yields compounds of formulaXXXI: ##STR34##

The latter are converted to their sodium salts via treatment with asuitable base, preferably sodium hydride or sodium amide, in an inertsolvent, preferably hexamethylphosphoric triamide or dimethyl sulfoxide,and allowed to react at 25° to 140° for 24 to 120 hours with thetriphenyl phosphorane (Wittig reagent) derived by treatment of any oneof the phosphonium salts represented by formula XXXII with a suitablestrong base such as sodium hydride:

    R.sup.14 CH.sub.2 -P.sup.+ (C.sub.6 H.sub.6).sub.3 X.sup.- XXXII

in compounds XXXII, R¹⁴ is methyl, ethyl, benzyloxyethyl or methoxy andX is a halide, preferably bromide or iodide. The Wittig condensationyields alkenes of formula XXXIII: ##STR35##

The latter, except where R¹⁴ is methoxy, are treated withm-chloroperbenzoic acid in methylene chloride at 0°-5° to yield oxiranesof the type represented by formula XXXIV: ##STR36##

These compounds are then treated with boron trifluoride etherate in aninert solvent, preferably ether or the like, at 0°-5° C. to yieldintermediate compounds XXXV: ##STR37## wherein R¹⁴ is methyl, ethyl, orbenzyloxyethyl.

Following removal of the benzyl blocking group by catalytichydrogenolysis using hydrogen over palladium on charcoal, the followingfinal products of structural formula I are obtained; namely, where R iscarboxyl, R¹ is acetyl, propionyl or 3-hydroxypropionyl, Z is ethylene,R² and R³ are hydrogen and A, R⁴, and R⁵ as defined previously.

Additional final products of structural formula I wherein R¹ is1,3-dihydroxypropyl and R, A, Z, R², R³, R⁴, and R⁵ are as defined aboveare obtained by selective ketone reduction of compounds of formula XXXVwherein R¹⁴ is 3-benzyloxypropionyl followed by subsequent debenzylationof the resulting carbinol diethers.

Final products of structural formula I in which R¹ is acryloyl and R, A,Z, R², R³, R⁴, and R⁵ are as defined above are obtained by exposure oftheir counterparts in which R¹ is 3-hydroxypropionyl to mild acidicconditions, preferably silicic acid.

Treatment of compounds of formula XXXIII wherein R¹⁴ is methoxy underacidic conditions followed by catalytic debenzylation provides finalproducts of formula I in which R¹ is formyl and R, A, Z, R², R³, R⁴, andR⁵ are as defined above.

DERIVATIZATION OF PRODUCTS FROM THE MAJOR PROCESSES

The directly obtained products of the acetoacetic, malonic and Wittigprocesses described supra can be derivatized in a variety of ways toyield other products of formula I.

1. The fundamental processes yield compounds where R is carboxy. Toobtain carboxy salts the acid products are dissolved in a solvent suchas ethanol, methanol, glyme and the like and the solution treated withan appropriate alkali or alkaline earth hydroxide or alkoxide to yieldthe metal salt, or with an equivalent quantity of ammonia, amine orquaternary ammonium hydroxide to yield the amine salt. In each instance,the salt either separates from the solution and may be separated byfiltration or, when the salt is soluble it may be recovered byevaporation of the solvent. Aqueous solutions of the carboxylic acidsalts can be prepared by treating an aqueous suspension of thecarboxylic acid with an equivalent amount of an alkaline earth hydroxideor oxide, alkali metal hydroxide, carbonate or bicarbonate, ammonia, anamine or a quaternary ammonium hydroxide.

To obtain carboxy esters (i.e., compounds where R is alkoxycarbonyl) theacid products are treated in ether with an ethereal solution of theappropriate diazoalkane. For example, methyl esters are produced byreaction of the acid products with diazomethane. To obtain productswhere R is carbamoyl, substituted carbamoyl or carbazoyl the acidproduct is first converted to an active Woodward ester. For example, theacid product can be made to react with N-tert-butyl-5-methylisoxazoliumperchlorate in acetonitrile in the presence of a base such astriethylamine to yield and active ester in which R is ##STR38##

Active esters of this type can be reacted with ammonia to yield productsof formula I where R is carbamoyl, with primary of secondary amine ofdi-lower-alkylaminoalkylamines to yield products where R is substitutedcarbamoyl, i.e., --CONR⁶ R⁷, and with hydrazine to yield products whereR is carbazoyl.

2. The fundamental processes yield products where R³ is hydrogen. Incompounds containing no additional hydroxy group and in which R² ishydrogen, reaction with formic acid, acetic anhydride, propionicanhydride, butyric anhydride, isobutyric anhydride, valeric anhydride,pivalic anhydride and the like, without solvent and at temperatures from25 to 60° C., gives compounds wherein R³ is formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, and pivaloyl, respectively.

3. It is to be noted that in the carboxylic acid products of thefundamental processes, R' is acyl; that is, R' contains a ketone oraldehyde carbonyl group; this group can be reduced to an alcoholicfunctional group by the action of sodium or potassium borohydride. Thefollowing transformations are hereby effected in R': acetyl becomes1-hydroxyethyl, hydroxyacetyl becomes 1,2-dihydroxyethyl, formyl becomeshydroxymethyl, and 3-hydroxypropionyl becomes 1,3-dihydroxypropyl. Thisreduction can be advantageously carried out by dissolving theacyl-containing compound in an aqueous or alcoholic solution of a basesuch as sodium hydroxide, sodium bicarbonate and the like and adding a20 to 100% excess of sodium or potassium borohydride. The reaction isallowed to proceed at a temperature of from 20° to 60° for a period of 2to 24 hours.

4. A related useful method of derivatization consists of treatment ofthe products of the fundamental processes with a large excess of aGrignard reagent, for example, methylmagnesium bromide. The carbonylgroup of R' is thereby converted to an alcohol functional group. Thefollowing transformations in R' take place, for example, withmethylmagnesium bromide: acetyl becomes 1-hydroxy-1-methylethyl;propionyl becomes 1-hydroxy-1-methylpropyl; formyl becomes1-hydroxyethyl.

In addition, products of the fundamental processes where R' is formyl,acetyl or propionyl and R² is hydrogen can be treated with an oxidizingagent, for example, chromium trioxide, to oxidize the secondaryalcoholic functional group (--C(R²)(OH)--) to a ketone carbonylfunctional group. The resulting diketone is treated with a large excessof Grignard reagent, for example, methylmagnesium bromide. The Grignardreagent reacts at both ketone carbonyl groups. For example, whenmethylmagnesium bromide is employed, a methyl R² group is introduced andR', if acetyl, is transformed to 1-hydroxy-1-methylethyl.

PREPARATION OF REAGENTS

1. The reagents VII A which have the following general formula whereinX, Z', R⁴ and R⁵ are as described previously are prepared by two relatedprocesses: ##STR39##

(a) When Z' is methylene, a Grignard reagent R⁵ --(CH₂)₂ --C(R⁴)₂--MgBr(or I) is allowed to react in ether or tetrahydrofuran with3-chloro- or 3-bromopropionaldehyde to give, after hydrolysis, thealcohols X--CH₂ CH₂ CH(OH)--C(R⁴)₂ --(CH₂)₂ --R⁵. Treatment of thealcohols with acetyl chloride or preferably acetic anhydride with orwithout an inert solvent and at 25°-100° C. gives the reagent VII Awhere Z' is methylene.

(b) When Z' is ethylene, trimethylene or tetramethylene, a Grignardreagent R⁵ --(CH₂)₂ --C(R⁴)₂ --MgBr(or I) is allowed to react in etheror tetrahydrofuran with a nitrile X--CH₂ --Z'--CN. The immediatelyresulting imine is hydrolyzed in aqueous acidic solution to give ketonesof the formula X--CH₂ --Z'--C(═O)--C(R⁴)₂ --(CH₂)₂ --R⁵. The ketones arereduced to the alcohols X--CH₂ --Z'--CH(OH)--C(R⁴)₂ --(CH₂)₂ --R⁵ withsodium or potassium borohydride in a suitable solvent such as methanol,ethanol or diglyme. Acetylation of these alcohols preferably with aceticanhydride as described previously gives the reagents VII A where Z' isethylene, trimethylene, or tetramethylene.

A variant of this process that is particularly useful when both R⁴groups are methyl consists in reacting Grignard reagents R⁵ --(CH₂)₂--C(CH₃)₂ --MgCl with acid chlorides X--CH₂ --Z'--C(═O)--Cl. Theresulting ketones X--CH₂ --Z'--C(═O)--C(CH₃)₂ --(CH₂)₂ --R⁵ are reducedto the alcohols X--CH₂ --Z'--CH(OH)--C(CH₃)₂ --(CH₂)₂ --R⁵ with sodiumor potassium borohydride and acetylated with acetic anhydride to givethe reagents VII A where Z' is ethylene, trimethylene or tetramethylene.

2. The reagents VII B which have the following general formula whereinR⁴ and R¹² are as described previously are prepared as follows:##STR40## A Grignard reagent R¹² --(CH₂)₂ --C(R⁴)₂ MgBr(or I or Cl) isallowed to react with crotonaldehyde to give, after hydrolysis, thealcohols CH₃ CH═CH--CH(OH)--C(R⁴)₂ (CH₂)₂ --R¹². These alcohols areacetylated, preferably with acetic anhydride without solvent at 30°-100°C. for 2-12 hours, to give the intermediates CH₃CH═CH--CH(OCOCH₃)--C(R⁴)₂ --(CH₂)₂ --R¹². These intermediates areallowed to react with N-bromosuccinimide in chloroform at 50°-70° C. for2.5 to 5 hours to effect allylic bromination and give the reagents offormula VII B.

3. The reagents VI C which have the following general formula whereinR², R⁴ and R¹² are as described previously are prepared as follows:##STR41## The starting materials for the process are aldehydes (when R²is hydrogen) or ketones with the structure R² --C(═O)--C(R⁴)₂ --(CH₂)₂--R¹². Examples of such aldehydes and ketones are hexanal,2-methylhexanal, 2-heptanone, and (when R¹² is joined either with R²when R² is methyl or with the carbon bearing R² when R² is hydrogen asearlier specified) cyclohexanone or cyclooctanone. Such aldehydes orketones are caused to react with lithium acetylide or ethynylmagnesiumbromide to give alcohols of the structure HC.tbd.C--C(R²)(OH)--C(R⁴)₂--(CH₂)₂ --R¹². These alcohols are acetylated preferably with aceticanhydride in pyridine solution. The resulting acetates are heated withformaldehyde (preferably introduced in the form of paraformaldehyde) anddimethylamine or diethylamine to give amines (Me)₂ N-- or (Et)₂ NCH₂C.tbd.C--C(R²)(OCOCH₃)--C(R⁴)₂ --(CH₂)₂ --R¹². The amines are caused toreact with cyanogen bromide preferably in ether solution at 25°-35° C.and for from 8 to 24 hours to give the reagents VI C.

The optically active reagents VII E with the following general formulain which R², R⁴ and R¹² are as defined previously and the carbon atommarked with an asterisk is exclusively in either the R or Sconfiguration are prepared by following exactly the procedures describedimmediately above. However, it is ##STR42## necessary in these cases toresolve into their R and S enantiomers the alcoholsHC.tbd.C--C(R⁴)(OH)--C(R⁴)₂ --(CH₂)₂ --R¹² and then carry the R and Senantiomers separately through the remaining steps of the procedure. Ina particularly advantageous example the alcohol arising from thereaction of lithium acetylide and hexanal, 1-octyn-3-ol,HC.tbd.C--CHOH--C₅ H₁₁ is resolved into its enantiomers according topublished procedures and these enantiomers converted to the R and Senantiomers of compound of formula VII E, i.e., BrCH₂C.tbd.C--CH(OCOCH₃)--C₅ H₁₁. The employment of these optically activereagents in the acetoacetic ester process gives rise to optically activeproducts of formula I, i.e., ##STR43## where the resolved asymmetriccarbon atom is marked with as asterisk. Hydrogenation of such productsgive rise to further optically active products of formula I, i.e.,##STR44##

4. The reagents VII D which have the following general formula whereinX, Z' and R¹² are as ##STR45## described previously are prepared asfollows: A Grignard reagent R¹² (CH₂)₂ CH₂ MgBr or R¹² (CH₂)₂ CH₂ MgI isallowed to react with haloketones XCH₂ --Z'--C(═O)CH₃ to give, afterhydrolysis, the tertiary alcohols X--CH₂ Z'--C(OH)(CH₃)--CH₂ (CH₂)₂ R¹².These alcohols can be dehydrated by treatment with a variety of acidicreagents and with heat to give the reagents VII C. A preferred method ofdehydration involves acetylation of the alcohols with acetic anhydride,and then heating the resulting esters in an inert solvent (benzene,toluene or the like) at from 80° to 140° in the presence of a trace ofan acid such as sulfuric or p-toluenesulfonic acid to effect eliminationof acetic acid.

5. The preparation of reagents of formula V has been described in thescientific and patent

    X(CH.sub.2).sub.4 ACOOR.sup.11                             V

literatures in instances where A is ethylene, trimethylene,α-methylethylene, β-methylethylene, α,α-dimethylethylene,β,β-dimethylethylene. To prepare reagents where A is oxymethylene, anester of glycolic acid, HOCH₂ COOR¹¹ is treated with a strong base,preferably sodium hydride, in a non-protic solvent (dimethylformamide,glyme and the like) and the resulting anion caused to react with a1,4-dihalobutane, preferably 1,4-dibromobutane. The glycolic ester andbase are employed in approximately equimolar quantities; a 1.5 to 2molar excess of the dihalobutane is advantageously used.

6. The reagents of formula XXVI ##STR46## wherein R¹¹, A and X are aspreviously defined, can be conveniently prepared from reagents V (seepreceeding section, 5) via conversion of V to the 2-substituteddithianes: ##STR47## employing 2-lithiodithiane in an inert solvent,preferably ether or tetrahydrofuran, at a temperature of -78° to -20°for a period of 2 to 24 hours. Oxidative cleavage of the latter in aninert aqueous medium provides half acids HOOC--(CH₂)₄ --A-COOR¹¹ whichare transformed to reagents of formula XXVI employing suitable acidhalide forming reagents which can be used without a solvent, preferablyoxalyl or thionyl chloride, at 20° to 100° for a period of 1 to 15hours.

7. The reagents illustrated by formula XXIX ##STR48## in which R⁴, R⁵,Z" and X are as previously defined in the section describing the Wittigroute, are readily prepared by the following transformations.Condensation of the Grignard reagents BrMg--C(R⁴)₂ --(CH₂)₂ --R⁵ with3-chloropropionaldehyde provides alcohols ##STR49## which may bereacted, without solvent, with s-trioxane and dry hydrogen chloride (g)at temperatures of -10° to 20° for a period of 2 to 12 hours to yieldchloromethyl ethers: The latter, upon metathesis with phenylmagnesiumbromide in an inert solvent, preferably benzene, ether ortetrahydrofuran, at a temperature of 0° to 40° for 2 to 24 hours,provide reagents XXIX.

8. The phosphonium salts of formula XXXII

    r.sup.14 --ch.sub.2 --p⊕--(c.sub.6 h.sub.5).sub.3 x⊖xxxii

can be prepared by allowing halides R¹⁴ --CH₂ --X, where R¹⁴ and X areas defined in the section describing the Wittig route, to react in theabsence of a solvent with triphenylphosphine at a temperature of 60° to120° for 12 to 200 hours. When R¹⁴ is 2-benzyloxyethyl, thecorresponding halide, ##STR50## may be prepared by transformation of3-bromopropanol to the corresponding chloromethyl ether followed bytreatment of the latter with phenylmagnesium bromide; these processeswere described previously in section 7.

Methods for obtaining optical antipodes of the compounds of thisinvention have been described supra [sections dealing with malonic acidprocess and preparation of intermediates (4)] whereby one of thecomponents of the molecule is preresolved prior to its assembly into thewhole molecule. Other methods also can be employed; for example,mixtures of racemates may be separated by taking advantage of thephysiochemical differences between the components using chromatographyand/or fractional crystallization. The racemic products andintermediates of this invention can be resolved into their opticallyactive components by any one of a number of methods of resolution whichare well described in the chemical literature.

Those compounds which are carboxylic acids can be converted to thediastereoisomeric salts by treatment with an optically active base suchas + or - α-methylbenzylamine, + or - α-(1-naphthyl)-ethylamine,bromine, cinchonine, cinchonidine, or quinine. These diastereoisomericsalts can be separated by fractional crystallization.

The carboxylic acids of this invention also can be converted to estersusing an optically active alcohol, such as, estradiol-3-acetate, or d-or l-menthol and the diastereoisomeric esters resolved bycrystallization or by chromatographic separation.

Racemic carboxylic acids also may be resolved by reverse phase andabsorption chromatography using an optically active support andabsorbent.

Compounds of this invention which contain free hydroxyl groups can beesterified with acid chlorides or anhydrides derived from opticallyactive acids, such as, (+)-10-camphorsulfonic acid,(+)-α-bromocamphor-πsulfonic acid, or d- or l-6,6'-dinitrodiphenic acidto form esters which can be resolved by crystallization.

Another method of obtaining pure optical isomers involves incubation ofthe racemic mixture with certain microorganisms such as fungi, byprocesses well established in the art, and recovering the product formedby the enzymatic transformation.

The methods described supra are especially effective if one applies theprocess to a compound where one asymmetric center has been preresolvedby the techniques already described.

EXAMPLE 1 Preparation of 8-Acetyl-12-hydroxyheptadecanoic Acid

Step A: Preparation of Ethyl 8-Tert.-butoxycarbonyl-9-oxodecanoate

A suspension of 57% sodium hydride in mineral oil (37.05 g. net wt.;0.88 mole) in a solvent mixture of benzene (400 ml.) anddimethylformamide (400 ml.) is treated, dropwise, over 30 minutes withtert.-butyl acetoacetate (126.56 g.; 0.80 mole). Stirring is continuedfor an additional 30 minutes. Then ethyl 7-bromoheptanoate (208.50 g.;0.88 mole) is added, dropwise, over 30 minutes and the mixture is heatedat 100° C. for 21/2 hours.

The cooled reaction mixture is treated with water (1600 ml.) and theorganic layer is separated. The aqueous layer is extracted with ether.The combined organic solutions are washed with saturated sodium chloridesolution and then dried over anhydrous sodium sulfate. The solvents areremoved under vacuum and the residual oil is distilled to give 158.6 g.(63%) of yellow oil, b.p. 175°-177°/0.5 mm.

Step B: Preparation of 1-Chloro-4-nonanone

To the Grignard reagent prepared from a mixture of amyl bromide (226.59g.; 1.5 moles) and magnesium (36.48 g.; 1.5 moles) in ether (1000 ml.)is added, dropwise, during one hour, 4-chlorobutyronitrile (155.34 g.;1.5 moles). Stirring is continued for an additional one hour. Thereaction mixture is poured into a mixture of finely crushed ice (1000g.) and concentrated hydrochloric acid (750 ml.). The ether layer isseparated quickly and discarded. The aqueous layer is heated on a steambath for one hour to hydrolyze the intermediate imine and cause theseparation of the ketone as an oil. After cooling, the oil is extractedwith ether and the combined extracts are washed with saturated sodiumchloride solution and dried over anhydrous sodium sulfate. The solventis removed under vacuum and the residual oil is distilled to give 69.0g. (26%) of colorless oil, b.p. 115°-117°/14 mm.; pmr (CDCl₃) δ0.90(3H,t), 3.56 (2H,t,CH₂ Cl).

Step B(2): Preparation of 1-Chloro-4-nonanol

A suspension of sodium borohydride (6.62 g.; 0.175 mole) and sodiumhydroxide (1.3 g.) in ethanol (310 ml.) is treated, dropwise, over 1hour with 1-chloro-4-nonanone (61.40 g.; 0.349 mole) while thetemperature is maintained at 45°-50°. Stirring is continued for onehour, longer without external cooling.

The reaction mixture is acidified with concentrated hydrochloric acid tothe Congo red endpoint and then the ethanol is removed under reducedpressure. The residue is treated with water (200 ml.) and the resultingoil is extracted with ether. The combined extracts are washed withsaturated sodium chloride solution and dried over anhydrous sodiumsulfate. The solvent is removed under vacuum to give the title compoundas a light yellow residual oil, yield 58.85 g.; ir (neat) 3400 cm⁻¹.

Step B(3): Preparation of 1-Chloro-4-acetoxynonane

A mixture of 1-chloro-4-nonanol (111.99 g.; 0.627 mole) and aceticanhydride (128.0 g.; 1.254 moles) is heated on a steam bath for 11/2hours.

The volatile materials are removed under reduced pressure and theresidual oil is distilled to give 88.6 g. (64%) of colorless oil, b.p.130°-133°/14 mm.;

pmr (CDCl₃) δ0.89 (3H,t), 2.02 (3H,s CH₃ COO), 3.53 (2H,t CH₂ Cl), 4.89(1H,m). Anal. Calcd. for C₁₁ H₂₁ ClO₂ : C, 59.85; H, 9.59 Found: C,59.87; H, 9.67.

Step B(4): Preparation of Ethyl8-Acetyl-8-tert.-butoxycarbonyl-12-acetoxyheptadecanoate

A suspension of 57% sodium hydride in mineral oil (3.03 g. net wt.,0.072 mole) in a solvent mixture of benzene (40 ml.) anddimethylformamide (40 ml.) is treated, dropwise, over a period of 30minutes with ethyl 8-tert.-butoxycarbonyl-9-oxodecanoate (20.41 g.,0.065 mole). Stirring is continued for an additional period of 30minutes. Then 1-chloro-4-acetoxynonane (15.80 g., 0.072 mole) is added,dropwise, over 30 min. Potassium iodide (50 mg.) is added and themixture heated at 100° for 66 hours.

The reaction mixture is cooled, treated with water (160 ml.) and theorganic layer separated. The aqueous layer is extracted with ether. Thecombined organic extracts are washed with a saturated aqueous sodiumchloride solution and then dried over anhydrous sodium sulfate. Thesolvents are removed by evaporation in vacuo to give a residual oil ofethyl 8-acetyl-8-tert.-butoxycarbonyl-12-acetoxyheptadecanoate. Theyield is 32.04 g.; pmr (CDCl₃) δ0.90 (3H,t), 1.45 (9H,s), 2.02 (3H,s CH₃COO), 2.12 (3H,s CH₃ CO), 4.13 (2H,q).

Step C: Preparation of Ethyl 8-Acetyl-12-acetoxyheptadecanoate

A mixture of ethyl8-acetyl-8-tert.-butoxycarbonyl-12-acetoxyheptadecanoate (32.04 g.;0.0643 mole), p-toluenesulfonic acid monohydrate (1.10 g.) and toluene(110 ml.) is heated under reflux for 18-22 hours. The CO₂ evolved isindicated by bubbling the gas into aqueous Ba(OH)₂.

The cooled reaction mixture is washed with saturated sodium bicarbonatesolution (25 ml.), saturated sodium chloride solution (2 × 25 ml.) andthen dried over anhydrous sodium sulfate. The solvent is removed undervacuum to give 26.69 g. (theory 25.63 g.) of a residual oil. The oil ispurified by column chromatography on silica gel with chloroform as aneluant. There is obtained 9.6 g. (38%) of ethyl8-acetyl-12-acetoxyheptadecanoate, pmr (CDCl₃) δ0.90 (3H,t), 2.02 (3H,sCH₃ COO), 2.12 (3H, s CH₃ CO), 4.13 (2H,q), 4.84 (1H, m HCOCOCH₃).

Anal. Calcd. for C₂₃ H₄₂ O₅ : C, 69.31; H, 10.62 Found: C, 69.47; H,10.83

Step D: Preparation of 8-Acetyl-12-hydroxyheptadecanoic Acid

Ethyl 8-acetyl-12-acetoxyheptadecanoate (12.21 g., 0.0306 mole) is addedto a solution of sodium hydroxide (3.67 g., 0.0918 mole) in water (17ml.) and methanol (153 ml.). The resulting solution is allowed to standfor 72 hours at 25° C. Most of the methanol is removed by evaporation invacuo. The residual solution is diluted with water (150 ml.) andextracted with ether. The aqueous layer is acidified to Congo red paperwith concentrated hydrochloric acid. The product, which separates as aviscous liquid, is extracted with ether. The ether extract is washedwith water.

The ether extract is dried over anhydrous sodium sulfate and evaporatedin vacuo to produce 9.65 g. (95%) of 8-acetyl-12-hydroxyheptadecanoicacid as a viscous yellow liquid. This material is purified by columnchromatography on silica gel with 2% methanol in chloroform as theeluant. There is obtained 6.9 g. (69%) of pure8-acetyl-12-hydroxyheptadecanoic acid as a colorless liquid, pmr (CDCl₃)δ0.88 (3H,t), 2.12 (3H, S CH₃ CO), 3.64 (1H, m HCOH), 6.65 (2H, s OH andCOOH).

Anal. Calcd. for C₁₉ H₃₆ O₄ : C, 69.47; H, 11.05 Found: C, 69.55; H,11.22

EXAMPLE 2 Preparation of 8-Acetyl-12-hydroxyheptadecanoic Acid

Step A: 1-Nonen-4-ol

Magnesium (60.6 g., 2.5 moles) is suspended by stirring in ether (500ml.) and the mixture cooled in an ice bath while allyl chloride (91.8g., 1.2 moles) is added dropwise during 2.5 hours. Hexanal (100 g., 1.0mole) is then added dropwise to the suspension of allyl magnesiumchloride during 1 hour. The reaction mixture is then stirred withoutcooling for an additional 1.5 hours.

The mixture is poured onto ice acidified with concentrated hydrochloricacid. The ether layer is separated, washed with water, and dried oversodium sulfate. The ether is evaporated and the crude product isdistilled to obtain 102.3 g. (72%) of colorless oil, b.p. 88°-90°/15 mm.

Step B: 4-Acetoxy-1-nonene

A mixture of 1-nonen-4-ol (87.5 g., 0.616 mole) and acetic anhydride(125.8 g., 1.23 moles) is heated at 100° for 1.5 hours. Distillation ofthe reaction mixture yields 93.2 g. (82%) of 4-acetoxy-1-nonene, acolorless oil, b.p. 89°-91°/14 mm.

Step C: 1-Bromo-4-acetoxynonane

A solution of 4-acetoxy-1-nonene (18.4 g., 0.1 mole) and benzoylperoxide (200 mg.) in hexane (125 ml.) is stirred and cooled in an icebath. Hydrogen bromide gas is bubbled into the solution until 9.0 g.(0.11 mole) is absorbed. This uptake of hydrogen bromide takes place in50 minutes. The solution is allowed to stand without cooling for 1.5hours. It is then washed with dilute sodium bicarbonate solution andwater and dried over sodium sulfate. The hexane is evaporated and theresidual oil distilled to obtain 13.8 g. (52%) of1-bromo-4-acetoxynonane, a colorless oil, b.p. 98°-100°/0.3 mm.; pmr(CDCl₃)δ0.87 (3H,t), 2.02 (3H,s, CH₃ COO), 3.42 (2H,t, BrCH₂), 4.91(1H,m,HC--O).

Step D: Preparation of Ethyl8-Acetyl-8-tert.-butoxycarbonyl-12-acetoxyheptadecanoate

The preparation of this compound is carried out as described in Example1, Step B(4), except that an equimolar quantity of1-bromo-4-acetoxynonane is used instead of the 1-chloro-4-acetoxynonane.

Step E: Preparation of Ethyl 8-Acetyl-12-acetoxyheptadecanoate

This preparation is carried out as described in Example 1, Step C.

Step F: Preparation of 8-Acetyl-12-hydroxyheptadecanoic Acid

This preparation is carried out as described in Example 1, Step D.

EXAMPLE 3 Preparation of 8-Acetyl-13-hydroxyheptadenoic Acid

Step A: Preparation of 1-Chloro-5-nonanone

This compound is prepared essentially by the same procedure as describedin Example 1, Step B, using the following reagents:

1-Bromobutane -- 51.66 g. (0.377 mole)

Magnesium -- 9.17 g. (0.377 mole)

Ether -- 380 ml.

5-Chlorovaleronitrile -- 44.19 g. (0.377 mole)

1-Chloro-5-nonanone is obtained as a colorless oil, yield 16.65 g.(25%), b.p. 125°-127°/13 mm.; pmr (CDCl₃)δ0.90 (3H,t), 3.53 (2H, t CH₂Cl).

Anal. Calcd. for C₁₉ H₁₇ ClO: C, 61.18; H, 9.70; Found: C, 60.96; H,9.63.

Step A(2): Preparation of 1-Chloro-5-nonanol

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(2), using the following reagents:

Sodium Borohydride -- 5.17 g. (0.136 mole)

Sodium Hydroxide -- 1.00 g.

Ethanol -- 240 ml.

1-Chloro-5-nonanone -- 48.10 g. (0.272 mole)

1-Chloro-5-nonanol is obtained as a colorless residual oil, yield 48.61g.; ir (neat) 3400 cm⁻¹.

Step A(3): Preparation of 1-Chloro-5-acetoxynonane

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(3), using the following reagents:

1-Chloro-5-nonanol -- 48.61 g. (0.272 mole)

Acetic anhydride -- 55.49 g. (0.544 mole)

1-Chloro-5-acetoxynonane is obtained as a colorless oil, yield 52.0 g.(87%), b.p. 130°-134°/13 mm.; pmr (CDCl₃)δ0.90 (3H,t), 2.03 (3H, s CH₃COO), 3.53 (2H,t CH₂ Cl), 4.89 (1H, m).

Anal. Calcd. for C₁₁ H₂₁ ClO₂ : C, 59.85; H, 9.59; Found: C, 59.98; H,9.95.

Step A(4): Preparation of Ethyl8-Acetyl-8-tert.-butoxycarbonyl-13-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4) (except a trace of potassium iodide is addedjust prior to heating and then the heating period at 100° is continuedfor 67 hours), using the following reagents:

Sodium hydride (57% in mineral oil) -- 5.90 g. net wt. (0.140 mole)

Benzene -- 65 ml.

Dimethylformamide -- 65 ml.

Ethyl 8-tert.-butoxycarbonyl-9-oxodecanoate -- 39.93 g. (0.127 mole)

1-Chloro-5-acetoxynonane -- 30.90 g. (0.140 mole)

Potassium iodide -- Trace

Ethyl 8-acetyl-8-tert.-butoxycarbonyl-13-acetoxyheptadecanoate isobtained as a residual oil, yield, 62.15 g.; pmr (CDCl₃)δ0.89 (3H,t),1.45 (9H,s), 2.20 (3H, s CH₃ COO), 2.10 (3H, s CH₃ CO), 4.13 (2H,g).

Step B: Preparation of Ethyl 8-Acetyl-13-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (except reflux time is 48 hours), using thefollowing reagents:

Ethyl 8-acetyl-8-tert.-butoxycarbonyl-13-acetoxyheptadecanoate -- 62.15g. (0.125 mole)

p-Toluenesulfonic acid monohydrate -- 2.20 g.

Toluene -- 220 ml.

Ethyl 8-acetyl-13-acetoxyheptadecanoate is obtained as a residual oil,yield 48.3 g. The oil is purified by column chromatography on silica gelwith chloroform as an eluant; pmr (CDCl₃)δ0.90 (3H,t), 2.03 (3H,s CH₃COO), 2.10 (3H, s CH₃ CO), 4.13 (2H,q).

Step C: Preparation of 8-Acetyl-13-hydroxyheptadecanoic Acid

This compound is prepared essentially by the same procedure as describedin Example 1, Step D, using the following reagents:

Ethyl 8-acetyl-13-acetoxyheptadecanoate -- 8.70 g. (0.0219 mole)

Sodium hydroxide -- 2.63 g. (0.0657 mole)

Water -- 12.5 ml.

Methanol -- 112.5 ml.

8-Acetyl-13-hydroxyheptadecanoic acid is obtained as a yellow oil, yield5.12 g. (71%); pmr (CDCl₃)δ0.90 (3H,t), 2.10 (3H,s CH₃ CO), 7.52 (2H, sOH, COOH).

Anal. Calcd. for C₁₉ H₃₆ O₄ : C, 69.47; H, 11.05; Found: C, 69.81; H,11.03.

EXAMPLE 4 Preparation of 8-Acetyl-14-hydroxyheptadecanoic Acid

Step A(1): Preparation of 1-Bromo-6-nonanone

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(1), using the following reagents:

1-Bromopropane -- 36.90 g. (0.30 mole)

Magnesium -- 7.30 g. (0.30 mole)

Ether -- 300 ml.

6-Bromocepronitrile -- 52.81 g. (0.30 mole)

1-Bromo-6-nonanone is obtained as a light yellow oil, yield 14.36 g.(23%), b.p. 133°-135°/13 mm.; pmr (CDCl₃)δ0.90 (3H,t), 3.43 (2H,t CH₂Br).

Step A(2): Preparation of 1-Bromo-6-nonanol

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(2), using the following reagents:

Sodium borohydride -- 3.82 g. (0.101 mole)

Sodium hydroxide -- 0.75 g.

Ethanol -- 180 ml.

1-Bromo-6-nonanone -- 44.74 g. (0.202 mole)

1-Bromo-6-nonanol is obtained as a light yellow residual oil, yield,42.76 g.; ir (neat) 3400 cm⁻¹ .

Step A(3): Preparation of 1-Bromo-6-acetoxynonane

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(3), using the following reagents:

1-Bromo-6-nonanol -- 42.76 g. (0.192 mole)

Acetic anhydride -- 39.17 g. (0.384 mole)

1-Bromo-6-acetoxynonane is obtained as a colorless oil, yield 32.2 g.(63%), b.p. 142°-145°/13 mm.; pmr (CDCl₃)δ0.90 (3H,t), 2.03 (3H,s, CH₃COO), 3.45 (2H,t, CH₂ Br), 4.93 (1H, m).

Step A(4): Preparation of Ethyl8-Acetyl-8-tert.-butoxycarbonyl-14-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4) (except a trace of potassium iodide is addedjust prior to heating and then the heating period at 100° is continuedfor 21 hours), using the following reagents:

Sodium hydride (57% in mineral oil) -- 5.10 g. net wt. (0.121 mole)

Benzene -- 55 ml.

Dimethylformamide -- 55 ml.

Ethyl 8-tert.-butoxycarbonyl-9-oxodecanoate -- 34.59 g. (0.110 mole)

1-Bromo-6-acetoxynonane -- 32.20 g. (0.121 mole)

Potassium iodide -- Trace

Ethyl 8-acetyl-8-tert.-butoxycarbonyl-14-acetoxyheptadecanoate isobtained as a residual oil, yield, 54.86 g.; pmr (CDCl₃)δ0.90 (3H,t),2.01 (3H,s CH₃ COO), 2.0 (3H,s CH₃ CO), 4.10 (2H, q).

Step B: Preparation of Ethyl 8-Acetyl-14-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (except reflux time is 23 hours), using thefollowing reagents:

Ethyl 8-acetyl-8-tert.-butoxycarbonyl-14-acetoxyheptadecanoate -- 54.86g. (0.110 mole)

p-Toluenesulfonic acid monohydrate -- 1.95 g.

Toluene -- 195 ml.

Ethyl 8-acetyl-14-acetoxyheptadecanoate is obtained as a residual oil,yield 43.84 g. The oil is purified by column chromatography on silicagel with chloroform as an eluant, pmr (CDCl₃)δ0.90 (3H,t), 2.03 (3H,sCH₃ COO), 2.10 (3H,s CH₃ CO), 4.12 (2H,q).

Step C: Preparation of 8-Acetyl-14-hydroxyheptadecanoic Acid

This compound is prepared essentially by the same procedure as describedin Example 1, Step D, using the following reagents:

Ethyl 8-acetyl-14-acetoxyheptadecanoate -- 9.20 g. (0.0231 mole)

Sodium hydroxide -- 2.80 g. (0.0700 mole)

Water -- 15 ml.

Methanol -- 140 ml.

8-Acetyl-14-hydroxyheptadecanoic acid is obtained as a yellow oil, yield6.1 g. (80%); pmr (CDCl₃)δ0.90 (3H,t), 2.10 (3H,s CH₃ CO), 6.90 (2H,sOH,COOH).

Anal. calcd. for C₁₉ H₃₆ O₄ : C, 69.47; H, 11.05; Found: C, 69.46; H,11.04.

EXAMPLE 5 Preparation of 8-Acetyl-11-hydroxyheptadecanoic Acid

Step A(1): Preparation of 1-Chloro-3-nonanol

To the Grignard reagent prepared from a mixture of 1-bromohexane (73.90g.; 0.460 mole) and magnesium (11.04 g.; 0.460 mole) in ether (450 ml.),is added, dropwise, during one hour, a solution of 3-chloropropanol(37.40 g.; 0.400 mole) in ether (200 ml.). Stirring and refluxing arecontinued for an additional one hour.

The reaction mixture is poured into a mixture of finely crushed ice (600g.) and concentrated hydrochloric acid (225 ml.). The ether layer isseparated washed well with water and dried over anhydrous sodiumsulfate. The solvent is removed under vacuum and the residual oil isdistilled to give 25.0 g. (35%) of yellow oil, b.p. 123°-126°/14 mm.;pmr (CDCl₃)δ0.88 (3H,t), 2.07 (1H,s OH), 3.67 (2H,t CH₂ Cl).

Step A(2): Preparation of 1-Chloro-3-acetoxynonane

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(3), using the following reagents:

1-Chloro-3-nonanol -- 106.7 g. (0.60 mole)

Acetic anhydride -- 122.40 g. (1.20 moles)

1-Chloro-3-acetoxynonane is obtained as a colorless oil, yield 115.9 g.(87%), b.p. 133°-135°/14 mm.; pmr (CDCl₃)δ0.88 (3H,t), 2.03 (3H,s CH₃COO), 3.53 (2H,t CH₂ Cl), 5.02 (1H,m).

Anal. Calcd. for C₁₁ H₂₁ ClO₂ : C, 59.85; H, 9.59; Found: C, 59.78; H,9.64.

Step A(3): Preparation of Ethyl8-Acetyl-8-tert.-butoxycarbonyl-11-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4), (except a trace of potassium iodide is addedjust prior to heating and then the heating period at 100° is continuedfor 20 hours), using the following reagents:

Sodium hydride (57% in mineral oil) -- 5.90 g. net wt. (0.140 mole)

Benzene -- 65 ml.

Dimethylformamide -- 65 ml.

Ethyl 8-tert.-butoxycarbonyl-9-oxodecanoate -- 39.93 g. (0.127 mole)

1-Chloro-3-acetoxynonane -- 30.90 g. (0.140 mole)

Potassium iodide -- Trace

Ethyl 8-acetyl-8-tert.-butoxycarbonyl-11-acetoxyheptadecanoate isobtained as a residual oil, yield 61.30 g.; pmr (CDCl₃)δ0.88 (3H,t),2.03 (3H,s CH₃ COO), 2.12 (3H,s CH₃ CO), 4.15 (2H,q).

Step B: Preparation of Ethyl 8-Acetyl-11-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (except reflux time is 65 hours), using thefollowing reagents:

Ethyl 8-acetyl-8-tert.-butoxycarbonyl-11-acetoxyheptadecanoate -- 61.30g. (0.123 mole)

p-Toluenesulfonic acid monohydrate -- 2.20 g.

Toluene -- 220 ml.

Ethyl 8-acetyl-11-acetoxyheptadecanoate is obtained as a residual oil,yield 48.6 g. The oil is purified by column chromatography on silica gelwith chloroform as an eluant; pmr (CDCl₃)δ0.88 (3H,t), 2.02 (3H,s CH₃COO), 2.10 (3H,s CH₃ CO), 4.13 (2H,q).

Step C: Preparation of 8-Acetyl-11-hydroxyheptadecanoic Acid

Ethyl 8-acetyl-11-acetoxyheptadecanoate (6.5 g., 0.016 mole) is added toa solution of sodium hydroxide (2.0 g., 0.05 mole) in water (9 ml.) andmethanol (81 ml.). The resulting solution is allowed to stand at roomtemperature for 71 hours.

Most of the methanol is then evaporated in vacuo. The residual solutionis diluted with water (80 ml.) and extracted with ether. The aqueouslayer is acidified with concentrated hydrochloric acid to the Congo Redendpoint. The product precipitates as an oil. It is purified by columnchromatography on silica gel with 4% methanol in chloroform as eluant.There is obtained 1.3 g. of colorless oil showing a single spot, Rf0.05, on thin-layer chromatography on silica gel with 5% methanol inchloroform as eluant. The nmr spectrum indicates that8-acetyl-11-hydroxyheptadecanoic acid exists in equilibrium with itshemiketal, 2-methyl-2-hydroxy-3-(6-carboxyhexyl)-6-hexyltetrahydropyran.pmr (CDCl₃)δ0.88 (3H,t), 2.13 (less than 2H,s, CH₃ CO), 3.6 (1H,mCH--O), 6.62 (2H,s, COOH, OH).

Anal. Calcd. for C₁₉ H₃₆ O₄ : C, 69.47; H, 11.05; Found: C, 69.50; H,11.23.

EXAMPLE 6 Preparation of 8-Acetyl-12-hydroxy-(E)-10-heptadecenoic Acid

Step A: Preparation of Diethyl 2-Acetylazelate

This compound is prepared essentially by the same procedure as describedin Example 1, Step A, using the following reagents:

Sodium hydride (57% in mineral oil) -- 3.58 g. net wt. (0.085 mole)

Benzene -- 40 ml.

Dimethylformamide -- 40 ml.

Ethyl acetoacetate -- 10.02 g. (0.077 mole)

Ethyl 7-bromoheptanoate -- 20.16 g. (0.085 mole)

Diethyl 2-acetylazelate is obtained as a light yellow oil, yield 15.4 g.(70%), b.p. 155°-157°/0.05 mm.; pmr (CDCl₃)δ2.20 (3H,s), 3.40 (1H,t),4.15 (4H,m).

Step B(1): Preparation of 1-Bromo-4-acetoxy-2-nonene

A mixture of 4-acetoxy-2-nonene (73.5 g., 0.4 mole), N-bromosuccinimide(80.0 g., 0.45 mole), and carbon tetrachloride (500 ml.) is boiled underreflux for 3 hours. The mixture is then cooled and the suspendedsuccinimide, removed by filtration. The carbon tetrachloride solution iswashed with dilute sodium bicarbonate solution and water, and is driedover sodium sulfate. The carbon tetrachloride is evaporated in vacuo andthe residual oil is distilled to yield 62 g. (59%) of1-bromo-4-acetoxy-2-nonene as a light yellow oil, b.p. 110°-112°/0.1 mm.

Step B(2): Preparation of Diethyl2-Acetyl-2-(4-acetoxy-2-nonen-1-yl)azelate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4) (except heating period at 100° is one hour),using the following reagents:

Sodium hydride (57% in mineral oil) -- 2.49 g. net wt. (0.0592 mole)

Benzene -- 30 ml.

Dimethylformamide -- 30 ml.

Diethyl 2-acetylazelate -- 15.40 g. (0.0538 mole)

1-Bromo-4-acetoxy-2-nonene -- 15.57 g. (0.0592 mole)

Diethyl 2-acetyl-2-(4-acetoxy-2-nonen-1-yl)azelate is obtained as aresidual oil, yield 25.21 g.; pmr (CDCl₃) δ 2.02 (3H,s CH₃ COO), 2.12(3H,s CH₃ CO), 4.16 (4H,m), 5.26 (1H,m), 5.50 (2H,m, CH═CH).

Step C: Preparation of 8-Acetyl-12-hydroxy-(E)-10-heptadecenoic Acid

A solution of diethyl 2-acetyl-2-(4-acetoxy-2-nonen-1-yl)azelate (22.9g., 0.049 mole) and sodium hydroxide (15.7 g., 0.392 mole) in water (150ml.) and ethanol (150 ml.) is boiled under reflux for 2 hours. Solventsare removed under reduced pressure, the residue is dissolved in water,and the solution extracted with ether. The aqueous layer is acidifiedwith concentrated hydrochloric acid to the Congo Red endpoint. The crudeproduct separates as an oil, weight 18.9 g.8-Acetyl-12-hydroxy-(E)-10-heptadecenoic acid is isolated in purecondition from the crude product by chromatography on silica gel with 4%methanol in chloroform as the eluant. There is obtained 3.5 g. of yellowoil showing a single spot, Rf 0.63, in thin layer chromatography (silicagel, 1% acetic acid in ether); pmr (CDCl₃) δ 0.88 (3H,t), 2.10 (3H,s,CH₃ C═O), 4.03 (1H,m HCO), 5.50 (2H,m, HC═CH), 6.58 (2H,s COOH, OH).

Anal. Calcd. for C₁₉ H₃₄ O₄ : C, 69.90; H, 10.50; Found: C, 70.17; H,10.70.

EXAMPLE 7 Preparation of 8-Propionyl-12-hydroxyheptadecanoic Acid

Step A: Preparation of Di-tert.-butyl (6-ethoxycarbonylhexyl)malonate

This compound is prepared by a procedure somewhat similar to thatdescribed in Example 1, Step A (except heating period at 100° is 41/2hours), using the following reagents:

Sodium hydride (57% in mineral oil) -- 8.84 g. net wt. (0.21 mole)

Benzene -- 95 ml.

Dimethylformamide -- 95 ml.

Di-tert.-butyl (6-ethoxycarbonylhexyl)malonate -- 41.09 g. (0.19 mole)

Ethyl 7-Bromoheptanoate -- 49.80 g. (0.21 mole)

Di-tert.-butyl (6-ethoxycarbonylhexyl)-malonate is obtained as aresidual oil, yield 70.78 g.

Step B: Preparation of Di-tert.-butyl2-(4-acetoxynonyl)-2-(6-ethoxycarbonylhexyl)malonate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4) (except heating period at 100° is 42 hours),using the following reagents:

Sodium hydride (57% in mineral oil) -- 8.84 g. net wt. (0.21 mole)

Benzene -- 95 ml.

Dimethylformamide -- 95 ml.

Di-tert.-butyl (6-ethoxycarbonylhexyl)malonate -- 69.70 g. (0.187 mole)

1-Chloro-4-acetoxynonane -- 46.35 g. (0.21 mole)

Di-tert.-butyl 2-(4-acetoxy nonyl)-2-(6-ethoxycarbonylhexyl)malonate isobtained as a residual oil, yield 104.12 g.; pmr (CDCl₃) δ 0.88 (3H,t),1.45 (18H,s), 2.00 (3H,s CH₃ COO), 4.12 (2H,q).

Step C: Preparation of Ethyl 8-Carboxy-12-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (Except reflux time is 91/2 hours), using thefollowing reagents:

Di-tert.-Butyl 2-(4-acetoxynonyl)-2-(6-ethoxycarbonylhexyl)malonate --104.12 g. (0.187 mole)

p-Toluenesulfonic acid monohydrate -- 3.30 g.

Toluene -- 330 ml.

Ethyl 8-carboxy-12-acetoxyheptadecanoate is obtained as a residual oil,yield 74.90 g. The oil is purified by column chromatography on silicagel with 2% methanol in chloroform as an eluant; pmr (CDCl₃) δ 0.88(3H,t), 2.02 (3H,s CH₃ COO), 4.12 (2H,q), 10.97 (1H,s COOH).

Anal. Calcd. for C₂₂ H₄₀ O₆ : C, 65.97; H, 10.07; Found: C, 66.24; H,10.29.

Step D: Preparation of Ethyl 8-Chlorocarbonyl-12-acetoxyheptadecanoate

A solution of ethyl 8-carboxy-12-acetoxyheptadecanoate (12.0 g., 0.03mole) and thionyl chloride (7.2 g., 0.06 mole) in benzene (50 ml.) isrefluxed for 2.5 hours. Volatile materials are removed by using a rotaryevaporator in vacuo. The residual product, ethyl8-chlorocarbonyl-12-acetoxyheptadecanoate, is a viscous liquid weighing12.5 g. (100%), ir (neat) 1790 cm⁻¹ (acid chloride C═O), 1730 cm⁻¹(ester C═O). This material is used directly in the next step.

Step E: Preparation of Ethyl 8-Propionyl-12-acetoxyheptadecanoate

A solution of ethylmagnesium bromide in ether (100 ml.) is prepared inthe usual manner from ethyl bromide (5.5 g.; 0.05 mole) and magnesium(1.2 g.; 0.05 mole). The solution is chilled to 5° and cadmium chloride(5.5 g.; 0.03 mole) is added. The mixture is stirred 10 minutes withoutcooling and then boiled under reflux for 30 min. Most of the ether isthen allowed to distill; benzene (100 ml.) is added and about half ofthis solvent is allowed to distill. The mixture is then diluted withbenzene (50 ml.), heated to reflux, and ethyl8-chlorocarbonyl-12-acetoxyheptadecanoate (12.5 g.; 0.03 mole) is added,dropwise, during 20 minutes. After a further reflux period of 2 hours,the mixture is cooled and treated with a 10% solution of sulfuric acid.The benzene layer is separated, washed with water and dried over sodiumsulfate. The benzene is evaporated leaving a residual oil.

The product, a yellowish oil, is purified not by distillation but bycolumn chromatography on silica gel with chloroform as eluant. There isobtained 6.2 g. of ethyl 8-propionyl-12-acetoxyheptadecanoate, showing asingle spot, Rf 0.23, on thin layer chromatography (silicagel-chloroform); pmr (CDCl₃) δ 2.04 (3H,s CH₃ COO), 2.32 (5H,m), 4.15(2H,q), 4.87 (1H,m,HCO). Anal. Calcd. for C₂₄ H₄₄ O₅ : C, 69.86; H,10.75 Found: C, 69.57; H, 10.83.

Step F: Preparation of 8-Propionyl-12-hydroxyheptadecanoic Acid

This compound is prepared essentially by the same procedure described inExample 1, Step D, using the following reagents:

Ethyl 8-propionyl-12-acetoxyheptadecanoate -- 6.0 g. (0.146 mole)

Sodium hydroxide -- 1.0 g. (0.025 mole)

Water -- 10 ml.

Methanol -- 70 ml.

8-Propionyl-12-hydroxyheptadecanoic acid is purified by columnchromatography on silica gel with chloroform as eluant. There wasobtained 2.4 g. of 8-propionyl-12-hydroxyheptadecanoic acid as a lightyellow oil showing a single spot, Rf 0.18, in thin layer chromatography(silica gel-3% methanol in chloroform); pmr (CDCl₃) δ 2.35 (5H,m), 3.55(1H,m,HCO), 6.70 (2H,s,COOH,OH).

Anal. Calcd. for C₂₀ H₃₈ O₄ : C, 70.13; H, 11.18; Found: C, 70.34; H,11.69.

EXAMPLE 8 Preparation of 8-(3-Hydroxypropionyl)-12-hydroxyheptadecanoicAcid

Step A: Preparation of Dimethyl 3-Oxosebacoate Methyl acetoacetate (81g., 0.7 mole) is added dropwise at 6° to a suspension of 57% sodiumhydride in mineral oil (25.8 g., 0.6 mole) in dry benzene (1.2 l.).After standing at 25° for 11/2 hours, the reaction mixture is treatedwith 7-carbomethoxyheptanoyl chloride (103.33 g., 0.5 mole), added over1/2 hour. The resulting colorless mixture is stored at 25° overnight,cooled to 0° and diluted with water. After separating the layers, theaqueous phase is acidified and extracted with benzene. The combinedorganic extract is washed with water until the washings are neutral,dried over magnesium sulfate and evaporated in vacuo leaving a paleyellow oil (154 g.).

The pale yellow oil is added to a solution of sodium methoxide (29.72g., 0.55 mole) in methanol (500 ml.) and allowed to stand at 25° for 48hours. After concentrating the reaction mixture in vacuo, the residualmass is partitioned between ether and water; the aqueous phase isacidified with 10% sulfuric acid. The organic extract is washed withwater until the washings are neutral, dried over magnesium sulfate anddistilled; the fraction with b.p. 137°-155°/0.2-0.3 mm. is redistilledto yield the title compound as a colorless liquid (64.5 g., 53%), b.p.150°-153°/0.2-0.3 mm.

Anal. Calcd. for C₁₂ H₂₀ O₅ : C, 59.00; H, 8.25; Found: C, 58.98; H,8.42.

Step B(1): 1-Chloro-3-octanol

To the Grignard reagent prepared from a mixture of 1-bromopentane (66.50g., 0.44 mole) and magnesium (10.7 g., 0.44 mole) in ether (450 ml.) isadded, dropwise with stirring during one hour, 3-chloropropanal (4.1 g.,0.44 mole) in ether (200 ml.) Stirring and refluxing are continued foran additional hour.

The reaction mixture is cooled and poured into a mixture of finelycrushed ice (600 g.) and concentrated hydrochloric acid (225 ml.). Theether layer is separated, washed well with water, and dried overanhydrous sodium sulfate. The solvent is removed by evaporation in vacuoand the residual oil distilled to give 36.0 g. (50%) of colorlessliquid, b.p. 113°-114°/14 mm. Hg. pressure; pmr (CDCl₃) δ 0.88 (3H,t),1.87 (2H,q), 2.18 (H,s), 3.67 (2H,t), and 3.76 (H,s).

Anal. Calcd. for C₈ H₁₆ ClO: Cl, 21.66; Found: Cl, 21.15.

Step B(2): 3-Chloromethoxy-1-chlorooctane

A slow stream of hydrogen chloride gas is passed into a mixture of1-chloro-3-octanol (35.5 g., 0.218 mole) and s-trioxane (6.55 g., 0.073mole) in a conical flask cooled to 0° C. and protected from atmosphericmoisture. The process requires about 31/2 hours. The resulting two-phasemixture is treated with anhydrous calcium chloride at 25° C. for 64hours. The upper aqueous phase is removed by this action. The solidmaterial is removed by filtration and the filtrate distilled to give the3-chloromethoxy-1-chlorooctane as a colorless liquid (28.2 g., 61%),b.p. 128°-130°/15 mm.; pmr (CDCl₃) δ 0.88 (3H,t), 1.98 (2H,q), 3.61(2H,t), 3.92 (H,m), and 5.51 (2H,s).

Anal. Calcd. for C₉ H₁₈ Cl₂ O: C, 50.72; H, 8.51; Cl, 33.26; Found: C,50.27; H, 8.58; Cl, 33.48.

Step B(3): Preparation of 3-Benzyloxy-1-chlorooctane

To the Grignard reagent prepared from bromobenzene (46.5 g., 0.296 mole)and magnesium (7.2 g., 0.296 mole) in ether (150 ml.) is added, dropwisewith stirring, 3-chloromethoxy-1-chlorooctane (63.0 g., 0.296 mole) inether (100 ml.). The resulting solution is stirred at 25° C. for 16hours, then refluxed for 11/4 hours, cooled to 0° and cautiously treatedwith ice water (200 ml.) with vigorous stirring. After separating thephases, the aqueous layer is extracted with ether (200 ml.) The combinedorganic phases are washed with water, then 5% aqueous potassiumcarbonate and finally with saturated aqueous sodium chloride solution.

The organic phase is dried over sodium sulfate and evaporated in vacuoleaving the crude product which is distilled in vacuo to give pure3-benzyloxy-1-chlorooctane, (61.4 g., 81% yield), b.p. 127° at 0.2 mm.Hg. pressure; pmr (CDCl₃) δ 0.88 (3H,t), 1.92 (2H,q), 3.61 (2H,t; H,b),4.50 (2H,s) and 7.29 (5H,s).

Anal. Calcd. for C₁₅ H₂₃ ClO: C, 70.71; H, 9.10; Found: C, 70.91; H,9.25.

Step B(4): Preparation of Methyl8-Oxo-9-methoxycarbonyl-12-benzyloxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4), (except sodium iodide is used as an alkylationcatalyst and the reaction period is extended to 44-45 hours,) employingthe following reagents:

Dimethyl 3-Oxosebacoate -- 24.43 g., (0.1 mole)

57% Sodium hydride in mineral oil -- 4.2 g., (0.1 mole)

3-Benzyloxy-1-chlorooctane -- 28.03 g., (0.11 mole)

Sodium iodide -- 0.2 g., (1.33 mmole)

N,n-dimethylformamide -- 50 ml.

Benzene -- 50 ml.

The title compound is obtained as a pale yellow oil (46.0 g., 100%); pmr(CDCl₃) δ 0.88 (3H,t), 3.55 (8H, 25 and m), 4.50 (2H,s) and 7.29 (3H,s).

Step C: Preparation of 8-Oxo-12-benzyloxyheptadecanoic Acid

A dispersion of methyl 8-oxo-9-carbomethoxy-12-benzyloxyheptadecanoate(46.0 g., 0.1 mole) and potassium hydroxide (12.9 g., 0.23 mole) inwater (150 ml.) is maintained at 5° for 41 hours. To the resultingmixture is added 2N hydrochloric acid (200 ml.) over one hour at 0°. Themixture is stored at 5° for one week, then diluted with water (150 ml.)and extracted with ether (2 × 300 ml.).

The organic extract is washed with saturated brine, dried over sodiumsulfate and evaporated in vacuo leaving a semi-solid residue which issuspended in chloroform (50 ml.). The insoluble solid is collected,washed with chloroform (2 × 25 ml.) and dried at 65° for 2 hours toprovide 3-oxosebacic acid (2.5 g.), 110°-111°.

The combined organic filtrate and washings is evaporated in vacuo to ayellow oil (42 g.) which is treated with a solution of potassiumhydroxide (16.8 g., 0.3 mole) in methanol (300 ml.). The resultingsolution is stirred at 25° for 17 hours and filtered to remove a traceof insoluble material. The filtrate is evaporated in vacuo to a yellowresidue which is suspended in water (200 ml.). The resulting suspensionis cooled to 0°, vigorously stirred and treated with concentrated HCl(30 ml.) added dropwise over 10 min. which initiates smoothdecarboxylation. The mixture is stirred at ambient temperature for 1/4hour, diluted with water (600 ml.) and extracted with ether (3 × 200ml.). The organic extract is washed with saturated brine, dried oversodium sulfate and evaporated in vacuo to a pale yellow oil which isapplied to a silica gel column (500 g.) with chloroform. Elution withchloroform (2.175 l.) provides impure material; continued elution withthe same eluant (3.1 l.) gives the title compound as a colorless oil(12.3 g., 32%); pmr (CDCl₃) δ 0.88 (3H,t), 4.50 (2H,s), 7.29 (5H,s) acid7.98 (H, b.s.).

Anal. Calcd. for C₂₉ H₃₈ O₄ : C, 73.80; H, 9.80; Found: C, 73.13; H,10.00.

Step D(1): Preparation of 3-Chloromethoxy-1-bromopropane

A slow stream of dry hydrogen chloride (g) is passed into a mixture of3-bromo-1-propanol (83.4 g., 0.6 mole) and s-trioxane (18.0 g., 0.2mole) contained in a conical flask cooled at 0° for 31/2 hours. Theresulting two-phase mixture is dried over calcium chloride (upper,aqueous phase is consumed by the drying agent) at 25° for 64 hours.,filtered and distilled to give the title compound (55.2 g., 50%) as acolorless liquid, b.p. 78°-80°/15 mm.; pmr (CDCl₃) δ 2.15 (2H,p), 3.49(2H,t), 3.82 (2H,t), and 5.49 (2H,s).

Anal. Calcd. for C₄ H₈ BrClO: C, 25.63; H, 4.30; Found: C, 25.85; H,4.36.

Step D(2): Preparation of 3-Benzyloxy-1-bromopropane

To the Grignard reagent prepared from bromobenzene (46.3 g., 0.294 mole)and magnesium (7.15 g., 0.294 mole) in ether (150 ml.) is added,dropwise over one hour at 0°, a solution of3-chloromethoxy-1-bromopropane (55.0 g., 0.294 mole) in ether (50 ml.).The resulting solution is stirred at 25° for 16 hours, then heated atreflux for 1/4 hour, cooled to 0° and cautiously treated with ice water(200 ml.) with vigorous stirring. After separating the phases, theaqueous layer is extracted with ether (200 ml.). The combined organicextract is washed with water, 5% potassium carbonate, water andsaturated brine, dried over sodium sulfate and evaporated in vacuoleaving a pale yellow oil (64.4 g., 96%) which is distilled to providethe title compound as a colorless liquid (92% recovery), b.p.140°-141°/14 mm.; pmr (CDCl₃) δ 2.12 (2H,p), 3.51 (2H,t), 3.60 (2H,t),4.50 (2H,t) and 7.31 (5H,s).

Anal. Calcd. for C₁₀ H₁₃ BrO: Br, 34.88; Found: Br, 35.26.

Step D(3): Preparation of 3-Benzyloxypropyltriphenylphosphonium Bromide

A solution of 3-benzyloxy-1-bromopropane (41.0 g., 0.18 mole) andtriphenylphosphine (52.4 g., 0.2 mole) in benzene (500 ml.) is stirredand heated at reflux for 92 hours. After removing the solvent in vacuo,the residual gum is dissolved in acetonitrile (50 ml.) providing a paleyellow solution which is diluted with ethyl acetate (400 ml.) toincipient cloudiness and stirred at 25° for 48 hours. Deposited crystalsare collected; the yield is 48 g. (53%). Recrystallization from ethylacetate-acetonitrile (4:1) provides colorless needles, m.p. 151°-152°;pmr (CDCl₃) δ 2.0 (2H,m), 3.78 (4H,m), 4.49 (2H,s), 7.29 (5H,s) and 7.70(15H,m).

Anal. Calcd. for C₂₅ H₂₈ BrOP: C, 68.44; H, 5.74; Found: C, 68.28; H,5.83.

Step D(4): Preparation of8-(3-Benzyloxypropylidenyl)-12-benzyloxyheptadecanoic Acid

A suspension of 57% sodium hydride in mineral oil (1.68 g., 40millimoles) and 3-benzyloxypropyltriphenylphosphonium bromide (9.83 g.,20 millimole) in hexamethylphosphoric triamide (HMPT) (60 ml.) isstirred at 25° C. for 30 minutes. The resulting yellow suspension isvigorously stirred and cautiously treated with a solution of8-oxo-12-benzyloxyheptadecanoic acid (7.81 g., 20 millimole) in HMPT (40ml.) over a period of 40 minutes at 25° C. The reaction mixture ismaintained at this temperature for another hour, then slowly warmed to100° and then kept at 100° for 64 hours.

After cooling to 0°, the reaction mixture is partioned between ice water(2 liters) containing concentrated hydrochloric acid (6 ml.) and ether(3 × 400 ml.). The combined organic extracts are washed with water andthen saturated brine. After drying over anhydrous sodium sulfate, theextract is evaporated in vacuo to give a liquid residue (13.8 g.) whichis applied to a silica gel column (250 g. 0.05-0.2 mesh, E. Merckmaterial) with chloroform. After eluting with chloroform (1825 ml.) the8-(3-benzyloxypropylidenyl)-12-benzyloxyheptadecanoic acid is obtainedas a colorless liquid (2.5 g., 23% yield); pmr (CDCl₃) δ 0.88 (3H,t),3.47 (2H,t: H bs.), 4.50 (2H,s), 5.15 (H,t) and 7.29 (5H,s).

Step E: Preparation of8-(4-Benzyloxy-1-nonyl)-8,9-oxido-11-benzyloxyundecanoic Acid

A solution of m-chloroperbenzoic acid (0.98 g., 4.84 millimole) inmethylene chloride (12 ml.) is added over 5 minutes to a solution of8-(3-benzyloxypropylidenyl)-12-benzyloxyheptadecanoic acid (2.3 g., 4.4millimoles) in methylene chloride (8 ml.). After stirring at 15° C. for4 hours, the resulting suspension is cooled to -15° C. and filtered. Thefiltrate is diluted with methylene chloride (40 ml.), washed with 10%aqueous sodium sulfate, water, saturated aqueous sodium chloride andthen dried over anhydrous sodium sulfate for 15 hours at 25° C. Thesolution is filtered and the filtrate is removed by evaporation invacuo, leaving the8-(4-benzyloxy-1-nonyl)-8,9-oxido-11-benzyloxyundecanoic acid as acolorless liquid in quantitative yield; pmr (CDCl₃) δ 2.86 (H,t).

Step F: Preparation of8-(3-Benzyloxypropionyl)-12-benzyloxyheptadecanoic Acid

Boron trifluoride etherate (5.6 ml., 44 millimole) is added to asolution of 8-(4-benzyloxy-1-nonyl)-8,9-oxido-11-benzyloxyheptadecanoicacid (2.37 g., 4.4 millimole) in ether (40 ml.) at 0° C. After stirringat 0° C. for 45 minutes, the resulting solution is partitioned betweenether (160 ml.) and saturated aqueous ammonium chloride (3 × 40 ml.).The organic extract is dried over anhydrous sodium sulfate, filtered andevaporated in vacuo to give8-(3-benzyloxypropionyl)-12-benzyloxyheptadecanoic acid (2.37 g., 100%yield); pmr (CDCl₃) δ 2.67 (2H,t, J=6 cps.) and 3.73 (2H,t, J=6 cps.).

Step G: Preparation of 8-(3-Hydroxypropionyl)-12-hydroxyheptadecanoicAcid . 1/3 Chloroformate

A magnetically stirred solution of8-(3-benzyloxypropionyl)-12-benzyloxyheptadecanoic acid (2.37 g., 4.4millimole) in ethanol (50 ml.) is subjected to hydrogenation atatmospheric pressure at 23° C. in the presence of a 10% palladium oncharcoal catalyst (0.3 g.) for one hour. The hydrogen uptake is 2.4 ml.(100% theory). The catalyst is removed by filtration and the solvent isremoved by evaporation in vacuo to give8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid . 1/3 chloroformateas a viscous, colorless liquid (1.55 g., 97% yield); pmr (CDCl₃) δ 0.88(3H, t), 2.03 (H,m), 2.32 (2H,t), 2.68 (2H,t, J=5.5 cps.), 3.65 (H,b.s.), 3.86 (2H,t, J=5.5 cps.), 5.50 (3H, exchangeable s) and 7.32(1/3H,s).

Anal. Calcd. for C₂₀ H₃₈ O₅.l/3 CHCl₃ : C, 61.29; H, 9.70; Found: C,61.21; H, 9.48; C, 61.02; H, 9.69.

EXAMPLE 9 Preparation of 8-(1-hydroxyethyl)-12-hydroxyheptadecanoic Acid

Sodium borohydride (57% in mineral oil) (0.76 g., 0.02 mole) isdissolved in a solution of 8-acetyl-12-hydroxyheptadecanoic acid(Example 1) (7.2 g., 0.022 mole) and sodium hydroxide (1.2 g., 0.03mole) in water (80 ml.). The resulting solution is allowed to stand atroom temperature for 23 hours, and is then acidified to Congo Red withconcentrated hydrochloric acid. The oily product is taken up in ether,washed with water, and dried over sodium sulfate. The ether isevaporated leaving 6.5 g. (90%) of8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid as a yellow oil.

The product is purified by chromatography on a column containing 120 g.of silica gel made up with chloroform. The column is eluted with 2%methanol in chloroform and finally with 4% methanol in chloroform.Fractions are pooled and evaporated to yield a fraction with Rf 0.17 onsilica gel thin layer plates with an eluant ofchloroform-methanol-acetic acid (97:2:1) (iodine vapor development). Thepurified product, a nearly colorless oil, weighs 4.1 g. (57%).

Anal. Calcd. for C₁₉ H₃₈ O₄ : C, 69.04; H, 11.59; Found: C, 68.74; H,12.03.

pmr (CDCl₃)δ 0.88 (3H,t), 1.13 (3H, d, CH₃ CHOH), 2.30 (2H, t, CH₂COOH); 3.70 (2H,m, HCOH), 5.56 (3H,s, OH and COOH).

EXAMPLE 10 Preparation of 8-Hydroxymethyl-12-hydroxyheptadecanoic Acid

Step A: Ethyl 8-Hydroxymethyl-12-acetoxyheptadecanoate

Ethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate (Example 7, Step D)(14.0 g., 0.0335 mole) is added all at once to a solution of sodiumborohydride (2.7 g., 0.07 mole) in dry diglyme (75 ml.). An exothermicreaction occurs with foaming and a rise in temperature to 55°. After 2hours, the reaction mixture is cooled in an ice bath and 10%hydrochloric acid is added dropwise until the mixture is acidic to CongoRed. Water (250 ml.) is then added; the oily product is extracted intoether, washed with water, and dried over sodium sulfate. The ether isevaporated to leave 12.2 g. of 8-hydroxymethyl-12-acetoxyheptadecanoateas a yellow oil. The product is used in the next step without furtherpurification.

Step B: 8-Hydroxymethyl-12-hydroxyheptadecanoic Acid

Ethyl 8-hydroxymethyl-12-acetoxyheptadecanoate (12.2 g., 0.0316 mole) isdissolved in a solution of sodium hydroxide (4.0 g., 0.10 mole) in water(20 ml.) and methanol (100 ml.), and the resulting solution is allowedto stand 64 hours at 25°. The methanol is then evaporated at reducedpressure, and the residual solution is diluted with water (150 ml.) andextracted with ether. The aqueous solution is acidified to Congo Redwith concentrated hydrochloric acid. The oily acid which separates istaken up in ether, washed with water, and dried over sodium sulfate. Theether is evaporated to leave 6.6 g. of8-hydroxymethyl-12-hydroxyheptadecanoic acid as a yellow oil.

The product is purified by column chromatography on silica gel (110 g.)with elution first with 2% methanol in chloroform followed by 4%methanol in chloroform. There is obtained 3.7 g. of8-hydroxymethyl-12-hydroxyheptadecanoic acid as a colorless oil showinga single spot, Rf 0.14, on silica gel thin layer chromatography withchloroform-methanol-acetic acid, 96:3:1, elution.

pmr (CDCl₃) δ 0.90 (3H,t), 2.32 (2H,t, CH₂ COOH), 3.55 (3H,m, CHOH andCH₂ OH), 5.1 (3H,m, OH and COOH).

Anal. Calcd. for C₁₈ H₃₆ O₄ : C, 68.31; H, 11.47; Found: C, 68.72; H,11.53.

EXAMPLE 11 Preparation of 8-Acetyl-12-hydroxy-16-methylheptadecanoicAcid

Step A: Preparation of 1-Chloro-8-methyl-4-nonanone

To the Grignard reagent prepared from a mixture of1-bromo-4-methylpentane (200.00 g.; 1.21 mole) and magnesium (29.43 g.;1.21 mole) in ether (800 ml.) is added, dropwise during one hour,4-chlorobutyronitrile (125.30 g., 1.21 mole). Stirring is continued foran additional one hour.

The reaction mixture is poured into a mixture of finely crushed ice (800g.) and concentrated hydrochloric acid (600 ml.). The ether layer isseparated quickly and discarded. The aqueous layer is heated on a steambath for one hour to hydrolyze the intermediate imine and cause theseparation of the ketone as an oil. After cooling, the oil is extractedwith ether and the combined extracts are washed with saturated sodiumchloride solution and dried over anhydrous sodium sulfate. The solventis removed under vacuum and the residual oil is distilled to give 23.3g. (10%) of colorless oil, b.p. 121°-122°/15 mm.; pmr (CDCl₃) δ 0.89(6H,d), 3.57 (2H,t CH₂ Cl).

Anal. Calcd. for C₁₀ H₁₉ ClO: C, 62.98; H, 10.04; Found: C, 62.86; H,10.20.

Step B: Preparation of 1-Chloro-8-methyl-4-nonanol

A suspension of sodium borohydride (2.31 g.; 0.061 mole) and sodiumhydroxide (0.5 g.) in ethanol (110 ml.) is treated dropwise, over onehour, with 1-chloro-8-methyl-4-nonanone (23.0 g., 0.121 mole) while thetemperature is maintained at 45-50. Stirring is continued for one hourlonger without external cooling.

The reaction mixture is acidified with concentrated hydrochloric acid tothe Congo Red endpoint and then the ethanol is removed under reducedpressure. The residue is treated with water (70 ml.) and the resultingoil is extracted with ether. The combined extracts are washed withsaturated sodium chloride solution and dried over anhydrous sodiumsulfate. The solvent is removed under vacuum to give the title compoundas a light yellow residual oil, yield 22.73 g.; ir (neat) 3400 cm⁻¹.

Step C: Preparation of 1-Chloro-4-acetoxy-8-methylnonane

A mixture of 1-chloro-8-methyl-4-nonanol (22.73 g.; 0.118 mole) andacetic anhydride (24.07 g.; 0.236 mole) is heated on a steam bath for11/2 hours.

The volatile materials are removed under reduced pressure and theresidual oil is distilled to give 14.58 g. (58%) of colorless oil, b.p.138°-139°/15 mm.; pmr (CDCl₃)δ 0.85 (6H,d), 2.02 (3H,s CH₃ COO), 3.53(2H, t CH₂ Cl), 4.92 (1H,m).

Step D: Preparation of Ethyl8-Acetyl-8-tert.-butoxycarbonyl-12-acetoxy-16-methylheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4) (except a trace of potassium iodide is addedjust prior to heating and the heating period at 100° is continued for 69hours), using the following reagents:

Sodium hydride--2.56 net wt. (0.0607 mole)

Benzene--30 ml.

Dimethylformamide--30 ml.

Ethyl 8-tert.-butoxycarbonyl-9-oxodecanoate--17.36 g. (0.0552 mole)(Example 1, Step A)

1-chloro-4-acetoxy-8-methylnonane--14.21 g. (0.0607 mole)

Potassium iodide--Trace

The title compound is obtained as a residual oil, yield 28.30 g.; pmr(CDCl₃) δ 0.87 (6H,d), 1.45 (9H,s), 2.01 (3H,s CH₃ COO), 2.10 (3H,s CH₃CO), 4.15 (2H,q).

Step E: Preparation of Ethyl 8-Acetyl-12-acetoxy-16-methylheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (except reflux time is 19 hours), using thefollowing reagents:

Ethyl8-acetyl-8-tert.-butoxycarbonyl-12-acetoxy-16-methylheptadecanoate--28.30g. (0.0552 mole)

p-Toluenesulfonic acid monohydrate--1.00 g.

Toluene--100 ml.

The title compound is obtained as a residual oil, yield 22.78 g. The oilis purified by column chromatography on silica gel with chloroform as aneluant, pmr (CDCl₃) δ 0.83 (6H,d), 2.02 (3H,s CH₃ COO), 2.10 (3Hs, CH₃CO), 4.07 (2H,q).

Anal. Calcd. for C₂₄ H₄₄ O₅ : C, 69.86; H, 10.75; Found: C, 70.00; H,10.97.

Step F: Preparation of 8-Acetyl-12-hydroxy-16-methylheptadecanoic acid

This compound is prepared essentially by the same procedure as describedin Example 1, Step D (except reaction solution is allowed to stand at60° for 161/2 hours), using the following reagents:

Ethyl 8-acetyl-12-acetoxy-16-methylheptadecanoate--11.2 g. (0.0272 mole)

Sodium hydroxide--3.2 g. (0.080 mole)

Water--20 ml.

Methanol--150 ml.

The title compound is obtained as a residual oil, yield 8.4 g. The oilis purified by column chromatography on silica gel with 2% methanol inchloroform as an eluant, pmr (CDCl₃) δ 0.88 (6H,d), 2.12 (3H,s CH₃ CO),3.62 (1H,m HCOH), 7.55 (2H,s OH, COOH).

Anal. Calcd. for C₂₀ H₃₈ O₄ : C, 70.13; H, 11.18; Found: C, 70.01; H,11.08.

EXAMPLE 12 Preparation of 8-Acetyl-12-hydroxynonadecanoic acid

Step A: Preparation of 1-Chloro-4-undecanone

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(1), using the following reagents:

1-Bromoheptane--214.94 g. (1.2 mole)

Magnesium--29.18 g. (1.2 mole)

Ether--800 ml.

4-Chlorobutyronitrile--124.27 g. (1.2 mole)

The title compound is obtained as a colorless oil, yield 60.4 g. (15%),b.p. 135°-140°/15 mm.; pmr (CDCl₃) δ 0.93, (3H,t), 3.57 (2H,t CH₂ Cl).

Step B: Preparation of 1-Chloro-4-undecanol

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(2), using the following reagents:

Sodium borohydride--5.56 g. (0.147 mole)

Sodium hydroxide--1.12 g.

Ethanol--265 ml.

1-Chloro-4-undecanone--60.00 g. (0.294 mole)

The title compound is obtained as a yellow residual oil, yield 60.02 g.

Step C: Preparation of 1-Chloro-4-acetoxyundecane

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(3), using the following reagents:

1-Chloro-4-undecanol--60.02 g. (0.29 mole)

Acetic anhydride--59.16 g. (0.58 mole)

The title compound is obtained as a colorless oil, yield 44.6 g. (62%),b.p. 155°-158°/15 mm.; pmr (CDCl₃) δ 0.88 (3H,t), 2.02 (3H,s CH₃ COO),3.53 (2H,t CH₂ Cl), 4.92 (1H,m).

Anal. Calcd. for C₁₃ H₂₅ ClO₂ : C, 62.76, H, 10.13; Found: C, 63.03; H,10.40.

Step D: Preparation of Ethyl8-Acetyl-8-tert.-butoxycarbonyl-12-acetoxynonadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4), (except a trace of potassium iodide is addedjust prior to heating and then the heating period at 100° is continuedfor 69 hours), using the following reagents:

Sodium hydride --3.47 net wt. (0.0825 mole) (57% in mineral oil)

Benzene--38 ml.

Dimethylformamide--38 ml.

Ethyl 8-Tert.-Butoxycarbonyl-9-oxodecanoate--23.58 g. (0.075 mole)(Example 1, Step A) 1-Chloro-4-acetoxyundecane--20.53 g. (0.0825 mole)Potassium iodide--Trace

The title compound is obtained as a residual oil, yield 39.52 g.; pmr(CDCl₃) δ 0.88 (3H,t), 1.45 (9H,s), 2.02 (3H,s CH₃ COO), 2.11 (3H,s CH₃CO), 4.13 (2H,q).

Step E: Preparation of Ethyl 8-Acetyl-12-acetoxynonadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (except reflux time is 22 hours), using thefollowing reagents:

Ethyl 8-acetyl-8-tert.butoxycarbonyl-12-acetoxynonadecanoate--39.52 g.(0.075 mole)

p-Toluenesulfonic acid monohydrate--1.35 g.

Toluene--135 ml.

The title compound is obtained as a residual oil, yield 30.1 g. The oilis purified by column chromatography on silica gel with chloroform as aneluant, pmr (CDCl₃) δ 0.88 (3H,t), 2.02 (3H,s CH₃ COO), 2.10 (3H,s CH₃CO), 4.13 (2H,q).

Anal. Calcd. for C₂₅ H₄₆ O₅ : C, 70.38; H, 10.87; Found: C, 70.17; H,11.04.

Step F: Preparation of 8-Acetyl-12-hydroxynonadecanoic acid

This compound is prepared essentially by the same procedure as describedin Example 1, Step D (except reaction solution is allowed to stand at60° for 16 hours), using the following reagents:

Ethyl 8-acetyl-12-acetoxynonadecanoate--14.00 g. (0.0329 mole)

Sodium hydroxide--3.95 g. (0.0987 mole)

Water--18.5 ml.

Methanol--166.5 ml.

The title compound is obtained as a residual oil, yield 10.57 g. The oilis purified by column chromatography on silica gel with 2% methanol inchloroform as an eluant, pmr (CDCl₃) δ 0.90 (3H,t), 2.11 (3H,s CH₃ CO),7.13 (2H,s OH, COOH).

Anal. Calcd. for C₂₁ H₄₀ O₄ : C, 70.74; H, 11.31; Found: C, 71.01; H,11.34.

EXAMPLE 13 Preparation of 2-Methyl-8-acetyl-12-hydroxyheptadecanoicaccid

Step A: 5-Acetoxypentyl chloride

Acetic anhydride (102 g., 1 mole) is added dropwise with stirring topentamethylene chlorohydrin (90 g., 0.74 mole). The resulting solutionis heated on the steam bath for one hour and allowed to stand overnightat room temperature. The reaction mixture is distilled to yield 83.6 g.(69%) of 5-acetoxypentyl chloride, b.p. 101°-104°/20 mm.

Step B: Diethyl (5-Acetoxypentyl)methylmalonate

Sodium hydride (4.8 g., 0.2 mole) as a 50% suspension in mineral oil iswashed with petroleum ether under nitrogen to remove the mineral oil,suspended in dry benzene (150 ml.), and the suspension cooled in an icebath . Diethyl methylmalonate (34.8 g., 0.2 mole) dissolved in sievedried DMF (150 ml.) is added to the suspension of sodium hydridedropwise. The mixture is allowed to stand overnight at room temperature.Potassium iodide (0.4 g.) and 5-acetoxypentyl chloride (32.9 g., 0.2mole) are then added, and the mixture is heated for 24 hours at 125° inan oil bath. The reaction mixture is concentrated in vacuo, diluted withether (200 ml.), and filtered to remove sodium chloride. The filtrate iswashed with brine, dried over anhydrous magnesium sulfate andconcentrated to yield 39.6 g. (66%) of oily product.

Step C: 7-Bromo-2-methylheptanoic acid

A mixture of the crude diethyl (5-acetoxypentyl)methylmalonate (68 g.0.23 mole) and 48% aqueous hydrobromic acid (100 ml.) is refluxed for 20hours. The mixture is then concentrated by distillation until theinternal temperature rises to 120°; 96 ml. of distillate (2 layers) iscollected. The residual liquid is cooled, dissolved in ether, washedwith brine, dried over magnesium sulfate, and the solution concentratedin vacuo to yield 54 g. of crude 7-bromo-2-methylheptanoic acid as adark viscous liquid.

Step D: Methyl 7-Bromo-2-methylheptanoate

A solution of crude 7-bromo-2-methylheptanoic acid (54 g., 0.24 mole)and concentrated sulfuric acid (2 drops) in absolute methanol (300 ml.)is refluxed for 5 hours. After standing overnight at room temperature,the solution is concentrated in vacuo and diluted with water. Themixture is made basic by the addition of saturated sodium carbonatesolution and the product taken up in ether. The ether extract is washedwith water, dried over anhydrous magnesium sulfate and distilled toyield 11.8 g. (16%) of methyl 7-bromo-2-methylheptanoate, b.p.67°-70°/0.05 mm.; pmr (CDCl₃) δ 1.13 (3H,d 2-CH₃), 2.42 (1H,m CHCOOCH₃),3.38 (2H,t CH₂ Br), 3.65 (3H,s CH₃ O).

Step E: Preparation of Methyl2-Methyl-8-tert.-butoxycarbonyl-9-oxodecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step A (except the heating period at 100° is continued for53/4 hours), using the following reagents:

Sodium hydride --3.75 g. net wt. (0.089 mole) (57% in mineral oil)

Benzene--40 ml.

Dimethylformamide--40 ml.

Tert.-Butyl Acetoacetate--12.81 g. (0.081 mole)

Methyl 7-Bromo-2-Methylheptanoate--21.01 g. (0.089 mole)

The title compound is obtained as a light yellow oil, yield 13.35 g.(52%), b.p. 168°-170°/0.05 mm.; pmr (CDCl₃) δ 1.13 (3H,d 2-CH₃), 1.45(9H,s), 2.20 (3H,s CH₃ CO), 3.27 (1H,t), 3.67 (3H,s CH₃ O).

Step F: Preparation of Methyl2-Methyl-8-acetyl-8-tert.butoxycarbonyl-12-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4) (except a trace of potassium iodide is addedjust prior to heating and the heating period at 100° is continued for 65hours), using the following reagents:

Sodium hydride --190 g. net. wt. (0.0453 mole) (57% in mineral oil

Benzene--25 ml.

Dimethylformamide--25 ml.

Methyl 2-methyl-8-tert.butoxycarbonyl-9-oxodecanoate--12.95 g. (0.0412mole)

1-Chloro-4-acetoxynonane --10.00 g. (0.0453 mole) (Example 1, Step B(3)

Potassium iodide--Trace

The title compound is obtained as a residual oil, yield 20.55 g.; pmr(CDCl₃) δ 1.13 (3H,d 2-CH₃), 1.45 (9H,s), 2.02 (3H,s CH₃ COO), 2.12(3H,S CH₃ CO), 3.67 (3H,s CH₃ O).

Step G: Preparation of Methyl 2-Methyl-8-acetyl-12-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (except reflux time is 22 hours), using thefollowing reagents:

Methyl2-methyl-8-acetyl-8-tert.-butoxycarbonyl-12-acetoxyheptadecanoate--20.55g. (0.0412 mole)

p-Toluenesulfonic acid monohydrate--700 mg.

Toluene--70 ml.

The title compound is obtained as a residual oil, yield 16.42 g. The oilis purified by column chromatography on silica gel with chloroform as aneluant, pmr (CDCl₃) δ 1.13 (3H,d 2-CH₃), 2.02 (3H,s CH₃ COO), 2.10 (3H,sCH₃ CO), 3.67 (3H,s CH₃ O), 4.82 (1H,m HCOCOCH₃).

Anal. Calcd. for C₂₃ H₄₂ O₅ : C, 69.31; H, 10.62; Found: C, 69.32; H,10.53.

Step H: Preparation of 2-Methyl-8-acetyl-12-hydroxyheptadecanoic acid

This compound is prepared essentially by the same procedure as describedin Example 1, Step D (except reaction solution is allowed to stand at25° for 70 hours), using the following reagents:

Methyl 2-Methyl-8-Acetyl-12-acetoxyheptadecanoate--11.0 g. (0.0277 mole)

Sodium hydroxide--3.4 g. (0.085 mole)

Water--35 ml.

Methanol--200 ml.

The title compound is obtained as a residual oil, yield 7.5 g. The oilis purified by column chromatography on silica gel with 2% methanol inchloroform as an eluant, pmr (CDCl₃), δ 0.88 (3H,t), 1.17 (3H,d 2-CH₃),2.12 (3H,s CH₃ CO), 3.60 (1H,m HCOH), 6.77 (2H,s OH, COOH).

Anal. Calcd. for C₂₀ H₃₈ O₄ : C, 70.13; H, 11.18; Found: C, 70.17; H,11.06.

EXAMPLE 14 Preparation of8-(1,3-Dihydroxypropyl)-12-hydroxyheptadecanoic acid

Step A: Preparation of8-(3-Benzyloxy-1-hydroxy-1-propyl)-12-benzyloxyheptadecanoic Acid

A clear, yellow solution of8-(3-benzyloxypropionyl)-12-benzyloxyheptadecanoic acid (2.55 g., 4.73millimole) (Example 8, Step F) and potassium hydroxide (0.3 g., 5.2millimole) in 90% aqueous methanol (20 ml.) is treated with potassiumborohydride (0.26 g., 4.73 millimole) providing a clear, pale yellowsolution which is stirred at 25° for 24 hours under nitrogen.

The reaction solution is heated at reflux for 2 hours and evaporated invacuo at 40° leaving a pale yellow oil which is treated with water (100ml.). The resulting turbid solution is cooled to 5°, acififiedcautiously (excess hydride is present) with concentrated HCl (5 ml.),stirred at ambient temperature for 15 minutes and extracted with ether(200 ml.). The organic extract is washed with saturated aqueous brine (2× 100 ml.) dried over sodium sulfate, filtered and evaporated in vacuoat 40° providing a crude oil (2.35 g., 92.3%); pmr (CDCl₃) δ 0.88(3H,t), 2.28 (2H,t), 3.28-3.92 (4H,m), 4.50, 4.63 (4H, 2s), 5.13 (2H,bs) and 7.32 (10H,s).

A sample of the oil (2.25 g.) is applied to a silica gel column (30 g.,0.05-0.2 mm., E. Merck, Darmstadt) with chloroform. Non-polar impurities(trace) are eluted with chloroform (85 ml.). Continued elution with thesame eluant (20 ml.) provides oil A (0.5 g.). Further elution with thesame eluant (125 ml.) followed by chloroform-methanol 95:5, 25 ml.)yields oil B (0.8 g.). Continued elution with the latter eluant (125ml.) gives oil C (1.04 g.). Pmr (CDCl₃) and tlc evaluation of oils A, B,and C indicate that they are essentially pure8-(3-benzyloxy-1-hydroxy-1-propyl)-12-benzyloxyheptadecanoic acidcontaminated with only small amounts of impurities and this material isadequate for use in the next step.

Step B: Preparation of 8-(1,3-Dihydroxypropyl)-12-hydroxyheptadecanoicacid

This compound is prepared essentially by the same procedure as describedin Example 8, Step G, employing the following reagents:

8-(3-Benzyloxy-1-Hydroxy-1-propyl)-12-benzyloxy-heptadecanoic acid, OilsA, B, and C described in Step A -- 2.2 g., 4.1 mmole

10% Palladium on Carbon -- 230 mg.

Hydrogen (g) (uptake) -- 210.3 ml.

Ethanol -- 34 ml.

The crude reduction mixture (1.55 g.) is applied to a silica gel column(30 g., 0.05-0.2 mm.; E. Merck, Darmstadt) with chloroform. Impuritiesare eluted with chloroform (260 ml.) followed by chloroform-methanol(98:2, 145 ml.) and chloroform-methanol (95:5, 60 ml.). Continuedelution with the latter eluant (225 ml.) provides oil A (0.5 g.) whichis a mixture of 8-(3-methoxy-1-hydroxy-1-propyl)-12-hydroxyheptadecanoicacid and 8,12-dihydroxyheptadecanoic acid.

Elution with chloroform-methanol (95:5, 125 ml.) followed bychloroform-methanol (9:1, 700 ml.) provides the crude title compound asviscous oil B (0.21 g.). Oil B is purified via application to apreparative thin layer plate (silica gel GF, 2,000 microns, Analtech)with chloroform. The plate is eluted with chloroform-methanol-aceticacid (8:1:1), air-dried and the separated components, visualized with au.v. lamp (u.v.s.-11, Mineral light). A band with Rf═0.47-0.57 isremoved and extracted with refluxing chloroform-methanol (9:1, 3 × 100ml.). The combined organic extract is evaporated in vacuo at 40°-60°providing the pure title compound as a viscous, pale yellow oil (80mg.); pmr (CDCl₃) δ 0.90 (3H,t), 1.37 (27H,e), 2.31 (2H, bs), 3.80 (4H,bs) and 5.63 (4H, exchangeable, bs).

Anal. Calcd. for C₂₀ H₄₀ O₅ : C, 66.62; H, 11.19; Found: C, 66.58; H,11.29.

EXAMPLE 15 Preparation of 9-Acetyl-12-hydroxyheptadecanoic Acid

Step A: Preparation of Ethyl 9-Tert.-butoxycarbonyl-10-oxoundecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step A (except a trace of potassium iodide is added justprior to heating and then the heating period at 100° is continued for 10hours), using the following reagents:

Sodium hydride (57% in mineral oil) -- 17.85 g. net wt. (0.424 mole)

Benzene -- 193 ml.

Dimethylformamide -- 193 ml.

Tert.-Butyl acetoacetate -- 60.19 g. (0.385 mole)

Ethyl 8-Bromooctanoate -- 106.30 g. (0.424 mole)

Potassium iodide -- Trace

The title compound is obtained as a residual oil, yield 126.45 g.; pmr(CDCl₃)δ 1.47 (9H,s), 2.22 (3H,s CH₃ CO), 3.33 (1H,t), 4.15 (2H,q).

Preparation of 1-Chloro-3-acetoxyoctane

Step 1: Preparation of 1-Chloro-3-octanol

This compound is prepared essentially by the same procedure as describedin Example 5, Step A(1), using the following reagents:

1-Bromopentane -- 113.71 g. (0.753 mole)

Magnesium -- 18.31 g. (0.753 mole)

Ether -- 1100 ml. (total)

3-Chloropropanol -- 69.70 g. (0.753 mole)

The title compound is obtained as a light yellow oil, yield 48.0 g.(39%), b.p. 110°-113°/14 mm.

Step B(2): Preparation of 1-Chloro-3-acetoxyoctane

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(3), using the following reagents:

1-Chloro-3-octanol -- 48.00 g. (0.29 mole)

Acetic Anhydride -- 59.16 g. (0.58 mole)

The title compound is obtained as a colorless oil, yield 47.0 g. (78%),b.p. 118°-120°/14 mm.; pmr (CDCl₃)δ 0.90 (3H,t), 2.05 (3H,s CH₃ COO),3.59 (2H,t CH₂ Cl), 5.07 (1H,m).

Anal. Calcd. for C₁₀ H₁₉ ClO₂ : C, 58.10; H, 9.26; Found: C, 58.68; H,9.45.

Step B(3): Preparation of Ethyl9-Acetyl-9-tert.-butoxycarbonyl-12-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4) (except a trace of potassium iodide is addedjust prior to heating and then the heating period at 100° is continuedfor 67 hours), using the following reagents:

Sodium hydride (57% in mineral oil) -- 9.60 g net wt. (0.228 mole)

Benzene -- 100 ml.

Dimethylformamide -- 100 ml.

Ethyl 9-tert.-butoxycarbonyl-10-oxoundecanoate -- 67.99 g. (0.207 mole)

1-Chloro-3-acetoxyoctane -- 47.00 g. (0.228 mole)

Potassium iodide -- Trace

The title compound is obtained as a residual oil, yield 97.1 g.; pmr(CDCl₃) δ 0.88 (3H,t), 1.45 (9H,s), 2.03 (3H,s CH₃ COO), 2.12 (3H,s CH₃CO), 4.15 (2H,q).

Step C: Preparation of Ethyl 9-Acetyl-12-acetoxyheptadecanoate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (except reflux time is 44 hours) using thefollowing reagents:

Ethyl 9-Acetyl-9-tert.-butoxycarbonyl-12-acetoxyheptadecanoate -- 97.10g. (0.195 mole)

p-Toluenesulfonic acid monohydrate -- 3.40 g.

Toluene -- 340 ml.

The title compound is obtained as a residual oil, yield 77.44 g. The oilis purified by column chromatography on silica gel with chloroform as aneluant; pmr (CDCl₃) δ 0.88 (3H,t), 2.03 (3H,s CH₃ COO), 2.12 (3H,s CH₃CO), 4.16 (2H,q).

Step D: Preparation of 9-Acetyl-12-hydroxyheptadecanoic Acid

Ethyl 9-acetyl-12-acetoxyheptadecanoate (13.5 g., 0.034 mole) isdissolved in a solution of sodium hydroxide (4.0 g., 0.10 mole) in water(40 ml.) and methanol (180 ml.). The resulting solution is heated at 60°for 20 hours. The methanol is then evaporated at reduced pressure. Theresidual solution is treated with 100 ml. water, extracted with ether,and the ether extract discarded. The aqueous solution is acidified withconcentrated hydrochloric acid. The oily product which separates istaken up in ether, washed with water and dried over sodium sulfate. Theether is evaporated leaving 9.5 g. of product as a viscous light yellowoil.

The product is purified by chromatography on a column containing 250 g.silica gel made up in chloroform. The product is eluted with 2% methanolin chloroform. There is obtained 4.0 g. of pure9-acetyl-12-hydroxyheptadecanoic acid exhibiting a single spot Rf 0.30on silica gel thin layer plates with chloroformmethanol-acetic acid,98:1:1 as eluant. The nmr spectrum indicates that this compound existsin equilibrium with its cyclic hemiketal.

Anal. Calcd. for C₁₉ H₃₆ 0₄ : C, 69.47; H, 11.05; Found: C, 69.93; H,11.26.

EXAMPLE 16 Preparation of 3-Methyl-8-acetyl-12-hydroxyheptadecanoic Acid

By replacing the ethyl 7-bromoheptanoate used in Example 1, Step A, withan equimolar quantity of methyl 3-methyl-7-iodoheptanoate thenconducting the synthesis as described in Example 1, Steps A, B(4), C,and D, there is obtained in sequence methyl3-methyl-8-tert.-butoxycarbonyl-9-oxodecanoate, methyl3-methyl-8-acetyl-8-tert.-butoxycarbonyl-12-acetoxyheptadecanoate,methyl 3-methyl-8-acetyl-12-acetoxyheptadecanoate, and3-methyl-8-acetyl-12-hydroxyheptadecanoic acid.

EXAMPLE 17 Preparation of 2,2-Dimethyl-8-acetyl-12-hydroxyheptadecanoicAcid

By replacing the ethyl 7-bromoheptanoate used in Example 1, Step A, withan equimolar quantity of methyl 2,2-dimethyl-7-iodoheptanoate thenconducting the synthesis as described in Example 1, Steps A, B(4), C,and D, there is obtained in sequence methyl2,2-dimethyl-8-tert.-butoxycarbonyl-9-oxodecanoate, methyl2,2-dimethyl-8-acetyl-8-tert.-butoxycarbonyl-12-acetoxyheptadecanoate,methyl 2,2-dimethyl-8-acetyl-12-acetoxyheptadecanoate, and2,2-dimethyl-8-acetyl-12-hydroxyheptadecanoic acid.

EXAMPLE 18 Preparation of 3,3-Dimethyl-8-acetyl-12-hydroxyheptadecanoicAcid

By replacing the ethyl 7-bromoheptanoate used in Example 1, Step A withan equimolar quantity of methyl 3,3-dimethyl-7-iodoheptanoate thenconducting the synthesis as described in Example 1, Steps A, B(4), C,and D, there is obtained in sequence methyl3,3-dimethyl-8-tert.-butoxycarbonyl-9-oxodecanoate, methyl3,3-dimethyl-8-acetyl-8-tert.-butoxycarbonyl-12-acetoxyheptadecanoate,methyl 3,3-dimethyl-8-acetyl-12-acetoxyheptadecanoate, and3,3-dimethyl-8-acetyl-12-hydroxyheptadecanoic acid.

EXAMPLE 19 Preparation of8-Acetyl-12-hydroxy-16,16-dimethylheptadecanoic Acid

The synthesis of this compound was carried out as described in Example1, except that in Step B(1), an equivalent amount of1-bromo-4,4-dimethylpentane is substituted for the amyl bromide. Thus,there is obtained in order: ethyl 8-tert.-butoxycarbonyl-9-oxodecanoate(Step A), 1-chloro-8,8-dimethyl-4-nonanone (Step B(1)),1-chloro-8,8-dimethyl-4-nonanol (Step B(2)),1-chloro-8,8-dimethyl-4-acetoxynonane (Step B(3)), ethyl8-acetyl-8-tert.-butoxycarbonyl-12-acetoxy-16,16-dimethylheptadecanoate(Step B(4)), ethyl 8-acetyl-12-acetoxy-16,16-dimethylheptadecanoate(Step C), and 8-acetyl-12-hydroxy-16,16-dimethylheptadecanoic acid.

EXAMPLE 20 Preparation of8-Acetyl-12-hydroxy-17,17,17-trifluoroheptadecanoate

The synthesis of this compound was carried out as described in Example1, except that in Step B(1), an equivalent amount of1,1,1-trifluoro-5-bromopentane is substituted for the amyl bromide.Thus, there is obtained in order: ethyl8-tert.-butoxycarbonyl-9-oxodecanoate (Step A),1-chloro-9,9,9-trifluoro-4-nonanone (Step B(1)),1-chloro-9,9,9-trifluoro-4-nonanol (Step B(2)),1-chloro-9,9,9-trifluoro-4-acetoxy nonane (Step B(3)), ethyl8-acetyl-8-tert.-butoxycarbonyl-12-acetoxy-17,17,17-trifluoroheptadecanoate(Step B(4)), ethyl 8-acetyl-12-acetoxy-17,17,17-trifluoroheptadecanoate,(Step C); and 8-acetyl-12-hydroxy-17,17,17-trifluoroheptadecanoic acid(Step D).

EXAMPLE 21 Preparation of 8-Acetyl-12-hydroxy-16-heptadecenoic Acid

The synthesis of this compound is carried out as described in Example 1,except that in Step B(1), an equivalent amount of 5-bromo-1-pentene isused in place of the amyl bromide. Thus, there is obtained in order:ethyl 8-tert.-butoxycarbonyl-9-oxodecanoate (Step A),1-chloro-8-nonen-4-one (Step B(1)), 1-chloro-8-nonen-4-ol (Step B(2)),1-chloro-4-acetoxy-8-nonene Step B(3)), ethyl8-acetyl-8-tert.-butoxycarbonyl-12-acetoxy-16-heptadecenoate (StepB(4)), ethyl 8-acetyl-12-acetoxy-16-heptadecenoate (Step C), and8-acetyl-12-hydroxy-16-heptadecenoic acid.

EXAMPLE 22 8-Acetyl-12-acetoxyheptadecanoic Acid

A mixture of 8-acetyl-12-hydroxyheptadecanoic acid (8.2 g., 0.025 mole)and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° for 18 hours.The mixture is then cooled and dissolved in 80 ml. ethyl ether. Thesolution is extracted with an ice-cold solution of 8 g. sodium hydroxidein 150 ml. water. The basic solution is separated and acidified withconcentrated hydrochloric acid. The oily acid which separates is takenup in ether, washed with water and dried over sodium sulfate. The etheris evaporated to leave 9.0 g. of the oily crude product.

The product is purified by chromatography on a column containing 150 g.of silica gel and with 1% methanol in chloroform as the eluting solvent.There is obtained 4.3 g. of 8-acetyl-12-acetoxyheptadecanoic acid, acolorless viscous oil; pmr (CDCl₃) δ 0.88 (3H,t), 2.04 (3H,s, CH₃ COO),2.10 (3H,s,CH₃ CO), 4.90 (1H,m, HCO), 10.7 (1H,s,COOH).

By substituting the acetic anhydride used in Example 22 with anequivalent amount of propionic anhydride, butyric anhydride, isobutyricanhydride, valeric anhydride, or pivalic anhydride and conducting thereaction as described in Example 22, there is obtained8-acetyl-12-propionyloxyheptadecanoic acid,8-acetyl-12-butyryloxyheptadecanoic acid,8-acetyl-12-isobutyryloxyheptadecanoic acid,8-acetyl-12-valeryloxyheptadecanoic acid, and8-acetyl-12-pivaloyloxyheptadecanoic acid, respectively.

EXAMPLE 23 8-Acetyl-12-formyloxyheptadecanoic Acid

A mixture of 8-acetyl-12-hydroxyheptadecanoic acid (8.2 g., 0.025 mole)and 97% formic acid (10 ml.) is heated at 60° for 24 hours. The mixtureis cooled, dissolved in 100 ml. ether, washed with 3 portions of waterand dried over sodium sulfate. Evaporation of the ether leaves theproduct 8-acetyl-12-formyloxyheptadecanoic acid as a slightly yellowishviscous oil.

EXAMPLE 24 Preparation of (5-Acetyl-9-hydroxytetradecyloxy)acetic Acid

Step A: Ethyl 4-Bromobutoxyacetate

Sodium hydride (9.0 g., 0.375 mole) is suspended in 1,2-dimethoxyethane.The mixture is stirred and cooled in an ice bath while ethyl glycollate(39.0 g., 0.375 mole) is added dropwise during one hour.1,4-Dibromobutane (108 g., 0.5 mole) is added all at once to theresulting thick suspension. The mixture is warmed gently to initiate astrongly exothermic reaction; then the mixture is heated 3 hours on thesteam bath. The mixture is poured into cold water. The heavy oil layeris taken up in ether, washed with three portions of water, and driedover sodium sulfate.

Evaporation of the ether and distillation of the residual oil yields21.3 g. (24%) of ethyl 4-bromobutoxyacetate, a colorless oil, b.p.99°-103°/0.2 mm.

Step B: Preparation of Ethyl(5-Tert.-butoxycarbonyl-6-oxoheptyloxy)acetate

This compound is prepared essentially by the same procedure as describedin Example 1, Step A (except a trace of potassium iodide is added justprior to heating and then the heating period at 100° is continued for 4hours), using the following reagents:

Sodium hydride (57% in mineral oil -- 3.75 g. net wt. (0.0887 mole)

Benzene -- 40 ml.

Dimethylformamide -- 40 ml.

Tert.-butyl acetoacetate -- 12.75 g. (0.0806 mole)

Ethyl (4-bromobutoxy) acetate -- 21.20 g. (0.0887 mole)

Potassium iodide -- Trace

The title compound is obtained as a light yellow oil, yield 15.35 g.(60%), b.p. 166°-168°/0.3 mm; pmr (CDCl₃) δ 1.48 (9H,s), 2.23 (3H,s CH₃CO), 4.07 (2H,s OCH₂ CO), 4.25 (2H,q).

Step C: Preparation of Ethyl(5-Acetyl-5-tert.-butoxycarbonyl-9-acetoxytetradecyloxy)acetate

This compound is prepared essentially by the same procedure as describedin Example 1, Step B(4) (except a trace of potassium iodide is addedjust prior to heating and then the heating period at 100° is continuedfor 69 hours) using the following reagents:

Sodium hydride (57% in mineral oil) -- 2.23 g. net wt. (0.0530 mole)

Dimethylformamide -- 25 ml.

Benzene -- 25 ml.

Ethyl (5-tert.-butoxycarbonyl-6-oxoheptyloxy) acetate -- 15.24 g.(0.0482 mole)

1-Chloro-4-acetoxy nonane -- 11.70 g. (0.0530 mole)

Potassium iodide -- Trace

The title compound is obtained as a residual oil, yield 24.13 g.; pmr(CDCl₃) δ 0.88 (3H,t), 1.45 (9H,s), 2.00 (3H,s CH₃ COO), 2.12 (3H,s CH₃CO), 4.05 (2H,s OCH₂ CO), 4.23 (2H,q).

Step D: Preparation of Ethyl (5-Acetyl-9-acetoxytetradecyloxy)acetate

This compound is prepared essentially by the same procedure as describedin Example 1, Step C (except reflux time is 46 hours), using thefollowing reagents:

Ethyl (5-acetyl-5-tert.-butoxycarbonyl-9-acetoxytetradecyloxy)acetate --24.13 g. (0.0482 mole)

p-Toluenesulfonic acid monohydrate -- 0.85 g.

Toluene -- 85 ml.

The title compound is obtained as a residual oil, yield 17.15 g. The oilis purified by column chromatography on silica gel with chloroform as aneluant; pmr (CDCl₃)δ 0.88 (3H,t), 2.02 (3H,s CH₃ COO), 2.11 (3H,s CH₃CO), 4.05 (2H,s OCH₂ CO), 4.23 (2H,q).

Step E: Preparation of (5-Acetyl-9-hydroxytetradecyloxy)-acetic Acid

This compound is prepared essentially by the same procedure as describedin Example 1, Step D (except reaction solution is allowed to stand at60°-65° for 171/2 hours), using the following reagents:

Ethyl (5-Acetyl-9-acetoxytetradecyloxy)acetate -- 13.30 g. (0.0332 mole)

Sodium hydroxide -- 3.98 g. (0.0996 mole)

Water -- 19 ml.

Methanol -- 171 ml.

The title compound is obtained as a residual oil, yield, 6.66 g. The oilis purified by column chromatography on silica gel with 2% methanol inchloroform as an eluant, pmr (CDCl₃) δ 0.90 (3H,t), 2.13 (3H,s CH₃ CO),4.08 (2H,s OCH₂ CO), 7.27 (2H,s OH, COOH).

Anal. Calcd. for C₁₈ H₃₄ O₅ : C, 65.42; H, 10.37; Found: C, 65.52; H,10.55.

EXAMPLE 25 Methyl 8-Acetyl-12-hydroxyheptadecanoate

A solution of diazomethane (approx. 2.5 g., 0.06 mole) in ether (100ml.) is mixed with a solution of 8-acetyl-12-hydroxyheptadecanoic acid(9.9 g., 0.03 mole) in ether (50 ml.). The resulting solution is allowedto stand 4 hours at room temperature. Acetic acid is then added todestroy the excess diazomethane and the solution is washed with dilutesodium bicarbonate solution and water and dried over sodium sulfate.Evaporation of volatile materials at reduced pressure yields methyl8-acetyl-12-hydroxyheptadecanoate, a colorless viscous oil.

EXAMPLE 26 Decyl 8-Acetyl-12-hydroxyheptadecanoate

Using the method of Example 25 but substituting an ether solution1-diazodecane for the ether solution of diazomethane there is obtaineddecyl 8-acetyl-12-hydroxyheptadecanoate, a colorless viscous oil.

EXAMPLE 27 Preparation ofN-[(2-Dimethylaminoethyl)]8-acetyl-12-hydroxyheptadecanamide·0.1chloroformate

A solution of 8-acetyl-12-hydroxyheptadecanoic acid (3.29 g., 10millimole), Example 1, Step D, triethylamine (1.74 ml., 12.5 millimole)and distilled water (18 ml., 1.0 mole) in acetonitrile (100 ml.) istreated with N-t-butyl-5-methylisoxazolium perchlorate (3.0 g., 12.5millimole). The resulting solution is evaporated in vacuo (wateraspirator) at 20°-23° for 4 hours providing a tacky residue which istriturated with water (150 ml.) at 0°-5° for 15 minutes. After decantingthe aqueous phase, the oily residue is dissolved in benzene-ether[(1:1), 200 ml.]. The organic extract is dried over sodium sulfate,filtered and evaporated in vacuo at 35°-40° providing the desired"active ester",N-t-butyl-3-(8-acetyl-12-hydroxyheptadecanoyloxy)crotonamide, as a paleyellow oil.

A solution of 2-dimethylaminoethylamine (0.88 g., 10 millimole) inacetonitrile (25 ml.) is added to a solution of the "active ester" inacetonitrile (25 ml.) providing a clear solution which is stirred at 25°for 17 hours. The solvent is removed in vacuo at 40°-50° leaving aresidual oil which is partitioned between ether (200 ml.) and water (2 ×100 ml.). The organic extract is washed with saturated brine (2 × 100ml.), dried over sodium sulfate, filtered and evaporated in vacuo at40°-50° providing a tan, crude oil.

The oil is partitioned between 5% hydrochloric acid (100 ml.) and ether(2 × 100 ml.). The aqueous acid phase is slowly basicified with sodiumbicarbonate (16.8 g., 0.2 mole), then with 40% aqueous sodium hydroxide(10 ml.) providing a heterogeneous mixture which is extracted with ether(200, 100 ml.). The organic extract is washed with saturated brine (200ml.), dried over sodium sulfate, filtered and evaporated in vacuo at40°-50° leaving the title compound as a pale yellow oil (2.8 g., 76%);pmr (CDCl₃) δ 0.88 (3H,t), 2.10 (3H,s), 2.22 (6H,s), 3.38 (5H,m), 4.09(H,s) and 7.11 (H,bt).

Anal. Calcd. for C₂₃ H₄₆ N₂ O₃ . 0.1 CHCl₃ : C, 67.57; H, 11.32; N,6.84; Found: C, 67.63; H, 11.38; N, 6.66.

EXAMPLE 28 Preparation of 8-Acetyl-12-hydroxyheptadecanoic AcidHydrazide

This compound is prepared essentially by the same procedure as describedin Example 19 except hydrazine is used rather than an aliphatic amineand the acid-hydrazine conjugation is effected at -15° employing thefollowing reagents:

8-Acetyl-12-hydroxyheptadecanoic Acid (Example 1, Step D) -- 3.29 g.,0.01 mole

Triethylamine -- 1.74 ml., 0.0125 mole

Distilled water -- 18 ml., 1.0 mole

N-t-Butyl-5-methylisoxazolium perchlorate -- 3.0 g., 0.0125 mole

Acetonitrile -- 150 ml.

Hydrazine.hydrate -- 0.5 g., 0.01 mole

The title compound is obtained as a pale yellow oil.

EXAMPLE 29 Preparation of 8-Glycoloyl-12-hydroxyheptadecanoic Acid

Step A: Preparation of Ethyl 8-Diazoacetyl-12-acetoxyheptadecanoate

Diazomethane (6 g., 0.143 mole) is generated via dropwise addition of asolution of Diazald® (43 g.) in ether (400 ml.) over 45 minutes to awarm (65%), stirred solution of potassium hydroxide (12 g., 0.214 mole)in carbitol-water (7:2, 90 ml.). The resulting yellow, etherealdiazomethane distillate is cooled to 0° and treated with a solution ofethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate (8.1 g., 0.02 mole)(Example 7, Step D), in ether (40 ml.) added over a period of 15minutes.

The resulting solution is maintained at 0° for 1 hour, then allowed toslowly evaporate at 20° over 22 hours to a total volume of 50 ml.Additional ether (200 ml.) is added to the reaction solution and againthe solvent is allowed to evaporate at 20° over 15 hours. The titlecompound is obtained as a deep yellow oil (8.4 g., 100%), ν_(max)^(neat) 2100, 1730 and 1645 cm⁻².

Step B: Preparation of Ethyl 8-Glycoloyl-12-acetoxyheptadecanoate

A clear, yellow solution of ethyl 8-diazoacetyl-12-acetoxyheptadecanoate(8.4 g., 0.02 mole) in dioxane (50 ml.) is vigorously stirred at 20° andtreated with 2N sulfuric acid (30 ml.) added dropwise over 5 minutes.The resulting turbid solution is warmed to and maintained at 65° for 30minutes. The reaction solution is cooled to 20°, diluted with water to atotal volume of one liter and extracted with ether (5 × 200 ml.). Theorganic extract is washed with water (2 × 200 ml.), 5% aqueous sodiumbicarbonate (200 ml.), water (200 ml.), and saturated brine (2 × 200ml.), dried over sodium sulfate and filtered. Evaporation (in vacuo at40°-65°) of the filtrate gives the title compound as a deep yellow oil(7.9 g., 96%), pmr (CDCl₃) δ 0.86 (3H,t), 1.28 (27H,e), 2.0 (3H,s), 2.25(3H,t), 3.36 (H,b), 4.10 (2H,q), 4.21 (2H,s) and 4.84 (H,b).

Step C: Preparation of 8-Glycoloyl-12-hydroxyheptadecanoic Acid

A clear, yellow solution of ethyl 8-glycoloyl-12-hydroxyheptadecanoate(7.9 g., 0.02 mole) and potassium hydroxide (2.24 g., 0.04 mole) in 90%aqueous methanol (50 ml.) is stirred at 25° under nitrogen for 20 hours.The reaction solution is evaporated in vacuo at 40° leaving a residualred oil which is dissolved in water (200 ml.). The resulting solution isacidified with concentrated hydrochloric acid (10 ml.) and extractedwith ether (2 × 200 ml.). The organic extract is washed with saturatedbrine (2 × 200 ml.), dried over sodium sulfate, filtered and evaporatedin vacuo at 40°-50° providing the title compound as a slightly impure,deep yellow oil (6.3 g., 92%).

EXAMPLE 30 Preparation of 8-(1,2-Dihydroxyethyl)-12-hydroxyheptadecanoicAcid

This compound is prepared essentially by the same procedure as describedin Example 9 employing the following reagents:

8-Glycoloyl-12-hydroxyheptadecanoic Acid (Example 29, Step C) -- 3.83g., 0.011 mole

Sodium borohydride -- 0.38 g., 0.01 mole

Sodium hydroxide -- 0.6 g., 0.015 mole

Water -- 40 ml.

The title compound is obtained as a pale yellow oil.

EXAMPLE 31 Preparation of 8-Formyl-12-hydroxyheptadecanoic Acid

Step A: Preparation of 8-Formyl-12-benzyloxyheptadecanoic Acid

This compound is prepared essentially by the same procedure as describedin Example 8, Step D(4), employing the following reagents:

8-Oxo-12-benzyloxyheptadecanoic Acid (Example 8, Step C) -- 7.81 g.,0.02 mole

Methoxymethyltriphenylphosphonium bromide -- 7.62 g., 0.02 mole

57% Sodium hydride in mineral oil -- 1.68 g., 0.04 mole

Hmpt -- 100 ml.

Concentrated hydrochloric acid -- 6 ml.

Water -- 2 l.

The title compound is obtained as a clear, colorless oil.

Step B: Preparation of 8-Formyl-12-hydroxyheptadecanoic Acid

This compound is prepared essentially by the same procedure as describedin Example 8, Step G, employing the following reagents:

8-Formyl-12-benzyloxyheptadecanoic acid -- 4.04 g., 0.01 mole

Hydrogen (g) -- 243 ml., 0.01 mole

10% Palladium on charcoal -- 0.4 g.

Ethanol -- 100 ml.

The title compound is obtained as a pale yellow oil.

EXAMPLE 32 Preparation of 8-Acryloyl-12-hydroxyheptadecanoic Acid

A solution of 8-(3-hydroxypropionyl)-12-hydroxyheptadecanoic acid . 1/3chloroformate (Example 8, Step G) (3.58 g., 0.01 mole) in chloroform (5ml.) is applied to a silica gel column (100 g., E. Merck, Darmstadt,0.05-0.2 mm.). The column is allowed to stand at 25° for 24 hours, theneluted with chloroform-methanol (98:2) to slowly elute the titlecompound as a pale yellow oil.

EXAMPLE 33 Preparation of 8-Acetyl-12-hydroxy-12-methylheptadecanoicAcid

Step A: Ethyl8-Acetyl-8-tert.-butoxycarbonyl-12-methyl-11-heptadecenoate

This compound is prepared essentially by the same procedure described inExample 1, Step B(4), except that the following reagents are used:

Sodium hydride -- 12.0 g. (0.285 mole) (57% in mineral oil)

Benzene -- 130 ml.

Dimethylformamide -- 130 ml.

Ethyl 8-tert.-butoxycarbonyl-9-oxodecanoate -- 81.4 g. (0.259 mole)

1-Chloro-4-methyl-3-nonene -- 62.4 g. (0.285 mole)

The title compound is obtained as an orange-red residual oil, yield124.4 g.; pmr (CDCl₃) δ 1.45 (9H,s), 2.12 (3H,s), 4.12 (2H,9), 5.15(1H,m HC═).

Step B: Ethyl 8-Acetyl-12-methyl-11-heptadecenoate

This compound is prepared essentially by the same procedure described inExample 1, Step C (except reflux time is 21 hours), using the followingreagents:

Ethyl 8-acetyl-8-tert.butoxycarbonyl-12-methyl-11-heptadecenoate --117.2 g. (0.259 mole)

p-Toluenesulfonic acid monohydrate -- 4.5 g.

Toluene -- 450 ml.

The title compound is obtained as a residual oil, yield 94.8 g. It ispurified by column chromatography on silica gel with chloroform aseluant. The purified product exhibits a single spot, Rf 0.73, on silicagel thin-layer chromatography plates developed with 1% methanol inchloroform; pmr (CDCl₃) 2.12 (3H,s), 4.12 (2H,q), 5.12 (1H,m, HC═).

Step C: Ethyl 8-Acetyl-12-hydroxy-12-methylheptadecanoate

Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12 ml.) andtetrahydrofuran (20 ml.) is added to give a suspension of a yellowsolid. Then, ethyl 8-acetyl-12-methyl-11-heptadecenoate (4.2 g., 0.012mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred atroom temperature for 24 hours. After 6 hours, the yellow suspended solidhas disappeared and a cloudy solution results. To the solution is added3M sodium hydroxide solution (12 ml.), followed by 0.5M sodiumborohydride solution is 3M sodium hydroxide (12 ml.). Liquids aredecanted from the precipitated mercury. The organic layer is taken up inether, washed with three portions of water and dried over sodiumsulfate. Evaporation of the ether leaves 4.4 g. of ethyl8-acetyl-12-hydroxy-12-methylheptadecanoate as a yellowish oil used inthe next step without further purification; pmr (CDCl₃) δ 0.88 (3H,t),1.13 (3H,s, CH₃ COH), 1.25 (3H,t, CH₃ CH₂ OCO--), 2.12 (3H,s, CH₃ CO),4.12 (2H,q).

Step D: 8-Acetyl-12-hydroxy-12-methylheptadecanoic Acid

This compound is prepared essentially by the same procedure described inExample 1, Step D, using the following reagents:

Ethyl 8-acetyl-12-hydroxy-12-methylheptadecanoate -- 4.2 g. (0.011 mole)

Sodium hydroxide -- 1.0 g. (0.025 mole)

Water -- 10 ml.

Methanol -- 50 ml.

The title compound is obtained as a colorless viscous oil, yield 3.5 g.It is purified by column chromatography on silica gel with chloroformelution; pmr (CDCl₃) δ 0.88 (3H,t), δ 1.13 (3H,s CH₃ COH), 2.12(3H,s,CH₃ CO), 7.25 (2H,s, OH and COOH).

EXAMPLE 34 Preparation of8-Acetyl-12-hydroxy-13,13-dimethylheptadecanoic Acid

Step A(1): Preparation of 1-Chloro-5,5-dimethyl-4-nonanone

Four hundred ml. of a solution in ether of 1,1-dimethylpentylmagnesiumchloride prepared from magnesium (24.3 g., 1.0 mole) and1-chloro-1,1-dimethylpentane (134.5 g., 1.0 mole) according to theprocedure of Whitmore and Badertscher [J. Am. Chem. Soc., 55, 1559(1933)] is added dropwise with stirring to 4-chlorobutyryl chloride (197g., 1.4 moles) in ether (400 ml.) during 6 hours. The reaction mixtureis stirred for an additional 12 hours. It is then poured into a mixtureof ice and dilute hydrochloric acid. The ether layer is separated,washed with water, and dried over sodium sulfate. The ether isevaporated and the residue distilled at aspirator vacuum through aVigreaux column to yield the product as a colorless oil.

Step A(2): Preparation of 1-Chloro-5,5-dimethyl-4-nonanol

By following the procedure described for 1-chloro-4-nonanol (Example 1,Step B(2)) but substituting 1-chloro-5,5-dimethyl-4nonanone for1-chloro-4-nonanone and continuing stirring and heating at 50° for 6hours, there is obtained 1-chloro-5,5-dimethyl-4-nonanol.

Step A(3): Preparation of 1-Chloro-4-acetoxy-5,5-dimethylnonane

By following the procedure described for 1-chloro-4-acetoxynonane(Example 1, Step B(3)) but substituting 1-chloro-5,5-dimethyl-4-nonanolfor 1-chloro-4-nonanol and continuing the steam bath heating for 4hours, there is obtained 1-chloro-4-acetoxy-5,5-dimethylnonane.

Step A(4): Preparation of Ethyl8-Acetyl-8-tert-butoxycarbonyl-12-acetoxy-13,13-dimethylheptadecanoate

This compound is prepared as described in Example 1, Step B(4) exceptthat 1-chloro-4-acetoxy-5,5-dimethylnonane is substituted for1-chloro-4-acetoxynonane. The product is obtained as a residual oilwhich is used in the next step without purification.

Step B: Preparation of Ethyl8-Acetyl-12-acetoxy-13,13-dimethylheptadecanoate

This compound is prepared as described in Example 1, Step C except thatethyl8-acetyl-8-tertbutoxycarbonyl-12-acetoxy-13,13-dimethylheptadecanoate issubstituted for ethyl8-acetyl-8-tert-butoxycarbonyl-12-acetoxyheptadecanoate. The product, aviscous yellowish oil, is purified by chromatography on silica gel withchloroform as eluant.

Step C: Preparation of 8-Acetyl-12-hydroxy-13,13-dimethylheptadecanoicAcid

This compound is prepared as described in Example 1, Step D, except thatethyl 8-acetyl-12-acetoxy-13,13-dimethylheptadecanoate is substitutedfor ethyl 8-acetyl-12-acetoxyheptadecanoate. The product is purified bychromatography on silica gel with 2% methanol in chloroform as eluantand is obtained as a colorless viscous oil.

EXAMPLE 35 Preparation of 8-Acetyl-12-hydroxy-10-heptadecynoic Acid

Step A(1): Preparation of 3-Acetoxy-1-octyne

1-Octyn-3-ol (100 g., 0.794 mole) is dissolved in pyridine (79 g., 1.0mole) and acetic anhydride (81.6 g., 0.80 mole) is added dropwise withstirring during 1 hour. The temperature rises to 45°. The solution isheated at 55° for 1 hour and is then cooled and poured into 200 ml.ice-cold 5% hydrochloric acid. The oily product is taken up in ether,washed with water and brine and dried over sodium sulfate. The ether isevaporated and the residual oil distilled to yield 106.4 g. (80%) of3-acetoxy-1-octyne, b.p. 91°-92°/15 mm.

Step A(2): Preparation of 1-Diethylamino-4-acetoxy-2-nonyne

A mixture of 3-acetoxy-1-octyne (58.5 g., 0.35 mole), diethylamine (28.5g., 0.39 mole), paraformaldehyde (13.8 g., 0.46 mole) and p-dioxane (60ml.) is heated on the steam bath under a reflux condenser for 17 hours.The resulting solution is cooled and diluted with 250 ml. of ether. Thesolution is extracted with 300 ml. of 5% hydrochloric acid. The acidicaqueous extract is made basic with 10% sodium hydroxide solution. Theliberated amine is taken up in ether, washed with water and brine anddried over sodium sulfate. The ether is evaporated and the residual oildistilled to yield 73.1 g. (89%) of 1-diethylamino-4-acetoxy-2-nonyne,b.p. 103°-109°/0.3 mm.

Anal. Calcd. for C₁₅ H₂₇ NO₂ : C, 71.10; H, 10.74; N, 5.33; Found: C,70.73; H, 11.03; N, 5.55.

Step A(3): Preparation of 1-Bromo-4-acetoxy-2-nonyne

A solution of 1-diethylamino-4-acetoxy-2-nonyne (50.6 g., 0.20 mole) andcyanogen bromide (21.2 g., 0.20 mole) in ether (250 ml.) is allowed tostand at 25°-27° for 18 hours. The ether solution is washed with 5%hydrochloric acid solution, water, and brine and dried over sodiumsulfate. The ether is evaporated and the residual oil distilled. After aforerun of diethylcyanamide, there is collected 34.1 g. (65%) of1-bromo-4-acetoxy-2-nonyne, b.p. 97°-105°/0.2 mm.

Anal. Calcd. for C₁₁ H₁₇ BrO₂ : C, 50.59; H, 6.56; Found: C, 50.54; H,6.49.

Step A(4): Preparation of Diethyl2-Acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate

This compound is prepared essentially by the same procedure described inExample 1, Step B(4) (except heating period at 100° is one hour) usingthe following reagents:

sodium hydride (57% in mineral oil) -- 3.4 g. (0.14 mole)

benzene -- 65 ml.

dimethylformamide -- 65 ml.

diethyl 2-acetylazelate (Ex. 6, Step A) -- 36.7 g. (0.128 mole)

1-bromo-4-acetoxy-2-nonyne -- 36.7 g. (0.14 mole)

The product is obtained as a residual oil, yield 59.5 g., which is usedin the next step without purification.

Step B: Preparation of 8-Acetyl-12-hydroxy-10-heptadecynoic Acid

A solution of diethyl 2-acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate (59.7g., 0.128 mole) and sodium hydroxide (30 g., 0.75 mole) in water (200ml.) and methanol (800 ml.) is heated at 60° for 16 hours. Most of themethanol is then distilled at reduced pressure and the residue isdissolved in water. The solution is acidified to Congo Red withhydrochloric acid and the oily product taken up in ether and dried oversodium sulfate. Evaporation of the ether leaves 41.1 g. of the crudeproduct as a reddish viscous oil. The product is purified bychromatography on 650 g. of silica gel with 2% methanol in chloroform aseluant. Fifteen grams of pure 8-acetyl-12-hydroxy-10-heptadecynoic acidis obtained as a yellow viscous oil; pmr (CDCl₃) δ 0.90 (3H,t), 2.20(3H,s CH₃ CO), 4.37 (1H,t HCO).

Anal. Calcd. for C₁₉ H₃₂ O₄ : C, 70.33; H, 9.94; Found: C, 70.38; H,9.94.

EXAMPLE 36 Preparation of 8-Acetyl-12-(S)-hydroxyheptadecanoic Acid

Step A(1): Preparation of 3(S)-Acetoxy-1-octyne

This compound is prepared as described in Example 35, Step A(1) exceptthat (S)-1-octyn-3-ol, [α]_(D) ²⁶ -6.4° (C 3.3, CHCl₃) is substitutedfor racemic 1-octyn-3-ol. 3(S)-Acetoxy-1-octyne has [α]_(D) ²⁶ -79° (C3.0, CHCl₃).

Step A(2): Preparation of 1-Diethylamino-4(S)-acetoxy-2-nonyne

This compound is prepared as described in Example 35, Step A(2), exceptthat 3(S)-acetoxy-1-octyne is substituted for racemic3-acetoxy-1-octyne. 1-Diethylamino-4(S)-acetoxy-2-nonyne has [α]_(D) ²⁶-80° (C 3.3, CHCl₃).

Step A(3): Preparation of 1-Bromo-4(S)-acetoxy-2-nonyne

This compound is prepared as described in Example 35, Step A(3), exceptthat 1-diethylamino-4(S)-acetoxy-2-nonyne is substituted for racemic1-diethylamino-4-acetoxy-2-nonyne. 1-Bromo-4(S)-acetoxy-2-nonyne has[α]_(D) ²⁶ -83° (C 3.7, CHCl₃).

Step A(4): Preparation of Diethyl2-Acetyl-2-[4(S)-acetoxy-2-nonyn-1-yl]azelate

This compound is prepared as described in Example 35, Step A(4), exceptthat 1-bromo-4(S)-acetoxy-2-nonyne is substituted for racemic1-bromo-4-acetoxy-2-nonyne. The product is obtained as a residual oilwith [α]_(D) ²⁶ -48.9° (C, 3.9, CHCl₃).

Step B: Preparation of 8-Acetyl-12-(S)-hydroxy-10-heptadecynoic Acid

This compound is prepared as described in Example 35, Step B, exceptthat diethyl 2-acetyl-2-[4(S)-acetoxy-2-nonyn-1-yl]azelate issubstituted for diethyl 2-acetyl-2-2-(4-acetoxy-2-nonyl-1-yl)azelate.The product is purified by chromatography on silica gel with 2% methanolin chloroform as eluant. It is obtained as a colorless viscous oil with[α]_(D) ²⁶ -1.94° (C, 3.5, CHCl₃).

Anal. Calcd. for C₁₉ H₃₂ O₄ : C, 70.33; H, 9.94; Found: C, 70.44; H,10.07.

Step C: Preparation of 8-Acetyl-12-(S)-hydroxyheptadecanoic Acid

8-Acetyl-12-(S)-hydroxy-10-heptadecynoic acid (18.0 g., 0.056 mole) and5% platinum on charcoal catalyst (2.5 g.) are placed in a mixture ofethyl acetate (50 ml.) and cyclohexane (100 ml.) and hydrogenated in aParr apparatus with an initial hydrogen pressure of 45 pounds per squareinch. The uptake of the required 2 molar equivalents of hydrogen iscomplete in 10 minutes. The catalyst is removed by filtration and thesolvents evaporated to leave the product as a light yellow oil weighing15 g. It is purified by chromatography on 200 g. of silica gel. There isobtained 10.8 g. of 8-acetyl-12-(S)-hydroxyheptadecanoic acid as anearly colorless viscous oil, [α]_(D) ²⁶ +1.0° (C 3.9, CHCl₃).

Anal. Calcd. for C₁₉ H₃₆ O₄ : C, 69.47; H, 11.05; Found: C, 69.65; H,11.44.

EXAMPLE 37 Preparation of 8-Acetyl-12-(R)-hydroxyheptadecanoic Acid

By following exactly the same procedures as described in Example 35 butbeginning with (R)-1-octyn-3-ol instead of racemic 1-octyn-3-ol, thereare obtained successively: Step A(1), 3-(R)-acetoxy-1-octyne, [α]_(D) ²⁶+70° (C 3.1, CHCl₃); Step A(2), 1-diethylamino-4-(R)-acetoxy-2-nonyne,[α]_(D) ²⁶ +74° (C 3.2, CHCl₃); Step A(3),1-bromo-4-(R)-acetoxy-2-nonyne, [α]_(D) ²⁶ +75° (C 3.2, CHCl₃); StepA(4), diethyl 2-acetyl-2-[4-(R)-acetoxy-2-nonyl-1-yl]azelate, [α]_(D) ²⁶+46° (C 3.7, CHCl₃); Step B, 8-acetyl-12-(R)-hydroxy-10-heptadecynoicacid, [α]_(D) ²⁶ +2.18° (C 3.8, CHCl₃);

Anal. Calcd. for C₁₉ H₃₂ O₄ : C, 70.33; H, 9.94; found: C, 70.58; H,9.92; Step C, 8-acetyl-12-(R)-hydroxyheptadecanoic acid, [α]_(D) ²⁶-0.79° (C 3.8, CHCl₃); Anal. Calcd. for C₁₉ H₃₆ O₄ : C, 69.47; H, 11.05;found: C, 69.19; H, 11.34.

EXAMPLE 38 Preparation of8-(1-Hydroxy-1-methylethyl)-12-hydroxy-12-methylheptadecanoic Acid

Step A: Preparation of 8-Acetyl-12-oxoheptadecanoic Acid

A solution of 8-acetyl-12-hydroxyheptadecanoic acid (9.85 g., 0.03 mole)in acetone (29 ml.) is cooled to 5°-10° and treated, dropwise, over 21/4hours with a solution prepared from a mixture of chromium trioxide (2.57g., 0.0257 mole) water (7.5 ml.) and concentrated sulfuric acid (2.1ml.). Stirring is continued for an additional 30 minutes.

The reaction mixture is filtered and the filtrate is diluted with water(240 ml.). The resulting oil is extracted with ether and the combinedextracts are washed with saturated sodium chloride solution and thendried over anhydrous sodium sulfate. The solvent is removed under vacuumto give the title compound as a light yellow residual oil, yield 9.10 g.(93%); pmr (CDCl₃) δ 0.88 (3H,t), 2.12 (3H,s), 2.38 (7H,m), 11.18 (1H,sCOOH).

Anal. Calcd. for C₁₉ H₃₄ O₄ : C, 69.90; H, 10.50; Found: C, 69.50; H,10.59.

Step B: Preparation of8-(1-Hydroxy-1-methylethyl)-12-hydroxy-12-methylheptadecanoic Acid

Magnesium (3.4 g., 0.14 mole) is placed in tetrahydrofuran (60 ml.) andmethyl bromide gas is bubbled into the mixture until all the magnesiumis consumed and a clear solution of methylmagnesium bromide results.This solution is stirred and kept cool by means of a 25° water bathwhile 8-acetyl-12-oxoheptadecanoic acid (9.3 g., 0.028 mole) intetrahydrofuran (30 ml.) is added dropwise over a period of 40 min.During this time, a white solid separates and the mixture becomesdifficult to stir. The mixture is heated at reflux for 45 minutes, thencooled, and poured into 200 ml. saturated ammonium chloride solution.The oily product which forms is taken up in ether, washed with water,and dried over sodium sulfate. On evaporation of the ether, there isobtained 10.0 g. of yellow oil. The product is isolated bychromatography on 200 g. of silica gel with 4% methanol in chloroform asthe eluant. The product isolated shows a single spot on the silica gelthin layer chromatographic plate with chloroform-methanol-acetic acid,97:2:1, Rf 0.15. The amount of8-(1-hydroxy-1-methylethyl)-12-hydroxy-12-methylheptadecanoic acidobtained is 4.0 g.; it is a very viscous yellowish oil; pmr (CDCl₃ )δ0.90 (3H,t), 1.17 (9H, s CH₃ COH), 2.37 (2H,t CH₂ COO), 4.76 (3H,s OHand COOH).

Anal. Calcd. for C₂₁ H₄₂ O₄ : C, 70.34; H, 11.81; Found: C, 70.61; H,12.01.

EXAMPLE 39 Preparation of8-Acetyl-11-(1-hydroxycyclohexyl)-10-undecynoic Acid

Step A(1): Preparation of 1-Acetoxy-1-ethynylcyclohexane

1-Ethynylcyclohexan-1-ol (100 g., 0.8 mole) is added dropwise withstirring to a mixture of acetic anhydride (86.7 g., 0.85 mole) andsulfuric acid (0.25 ml.). The temperature of the reaction mixture iskept at 10°-12° during the addition by means of an ice bath. The mixtureis then stirred without cooling for 1.5 hours. It is then poured into300 ml. of ice water. The oily product is taken up in ether, washed withwater, dilute sodium bicarbonate solution and brine and dried oversodium sulfate. Distillation affords 107 g. (80%) of1-acetoxy-1-ethynylcyclohexane, b.p. 95°-97°/15 mm.

Step A(2): Preparation of1-Acetoxy-1-(3-diethylamino-1-propynyl)cyclohexane

A mixture of 1-acetoxy-1-ethynylcyclohexane (64.00 g., 0.385 mole),diethylamine (30.95 g., 0.424 mole), paraformaldehyde, (15.00 g.; 0.500mole), cuprous chloride (1.5 g.) and dioxane (60 ml.) is stirred well.An exothermic reaction gradually results which may require externalcooling to prevent spillage. After this initial reaction, the mixture isheated on a steam bath for 11/2 hours.

The cooled reaction mixture is treated with ether and the product isextracted into ice-cold 5% hydrochloric acid. This cold aqueous acidicsolution is then basified with ice-cold 10% sodium hydroxide. The oilyamine is extracted with ether and the combined extracts are washed withsaturated sodium chloride solution and then dried over anhydrous sodiumsulfate. The solvent is removed under vacuum and the residual oil isdistilled to give 72.7 g. (75%) of light yellow oil, b.p. 113°-115°/0.15mm.; pmr (CDCl₃)δ 1.07 (6H,t), 2.02 (3H,s CH₃ COO), 2.60 (4H,q CH₃ CH₂N), 3.52 (2H,s CH₂ C.tbd.).

Step A(3): Preparation of 1-Acetoxy-1-(3-bromo-1-propynyl)-cyclohexane

Cyanogen bromide (31.8 g., 0.3 mole) is added to a solution of1-acetoxy-1-(3-diethylamino-1-propynyl)cyclohexane (61 g., 0.24 mole)and the resulting solution is allowed to stand at 25°-27° for 18 hours.The ether solution is washed with 5% hydrochloric acid solution, waterand brine and dried over sodium sulfate. The ether is evaporated and theresidual oil distilled. There is obtained 34.8 g. (55%) of1-acetoxy-1-(3-bromo-1-propynyl)-cyclohexane, a slightly yellowish oil,b.p. 114°-120°/0.2 mm.

Step A(4): Preparation of Diethyl2-Acetyl-2-[3-(1-acetoxycyclohexyl)-2-propyn-1-yl]azelate

This compound is prepared essentially by the same procedure described inExample 35, Step A(4) except that1-acetoxy-(3-bromo-1-propynyl)cyclohexane is substituted for1-bromo-4-acetoxy-2 -nonyne. The product is obtained as an orangeresidual oil which is used in the next step without purification.

Step B: Preparation of 8-Acetyl-11-(1-hydroxycyclohexyl)-10-undecynoicAcid

This compound is prepared by the same procedure described in Example 35,Step B, except that diethyl2-acetyl-2-[3-(1-acetoxycyclohexyl)-2-propyn-1-yl]azelate is substitutedfor diethyl 2-acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate. Thechromatographically purified product is a yellowish viscous oil; pmr(CDCl₃)δ 2.14 (3H,s CH₃ C0), 6.50 (2H,s OH and COOH).

Anal. Calcd. for C₁₉ H₃₀ O₄ : C, 70.77; H, 9.38; Found: C, 70.75; H,9.78.

EXAMPLE 40 Preparation of 8-Acetyl-11-(1-hydroxycyclohexyl)undecanoicAcid

This compound is prepared essentially by the same hydrogenationprocedure described in Example 36, Step C, except that8-acetyl-11-(1-hydroxycyclohexyl)-10-undecynoic acid (Example 39) issubstituted for 8-acetyl-12(S)-hydroxy-10-heptadecynoic acid. Theproduct is obtained as a yellowish viscous oil; pmr (CDCl₃)δ 2.08 (3H,sCH₃ CO), δ 6.52 (2H,s OH and COOH). Anal. Calcd. for C₁₉ H₃₄ O₄ : C,69.90; H, 10.50; Found: C, 70.23; H, 10.70.

EXAMPLE 41 Preparation of8-Acetyl-11-(1-hydroxycyclooctyl)-10-undecynoic Acid

By the use of the procedures described in Example 39 but starting with1-ethynylcyclooctan-1-ol in Step A(1) instead of1-ethynylcyclohexan-1-ol, there are obtained successively: Step A(1),1-acetoxy-1-ethynylcyclooctane; Step A(2),1-acetoxy-1-(3-diethyl-amino-1-propynyl)cyclooctane; Step A(3),1-acetoxy-1-(3-bromo-1-propynyl)cyclooctane; Step A(4), diethyl2-acetyl-2-[3-(1-acetoxycyclooctyl)-2-propyn-1-yl]azelate; Step B,8-acetyl-11-(1-hydroxycyclooctyl)-10-undecynoic acid.

EXAMPLE 42 Preparation of 8-Acetyl-11-(1-hydroxycyclooctyl)undecanoicAcid

This compound is prepared essentially by the same hydrogenationprocedure described in Example 36, Step C, except that8-acetyl-11-(1-hydroxycyclooctyl)-10-undecynoic acid (Example 41) issubstituted for 8-acetyl-12(S)-hydroxy-10-heptadecynoic acid. Theproduct is obtained as a colorless viscous oil.

EXAMPLE 43 Preparation of8-(1-Hydroxyethyl)-12-hydroxy-(E)-10-heptadecenoic Acid

This compound is prepared by the method described in Example 9 exceptthat 8-acetyl-12-hydroxy-(E)-10-heptadecenoic acid is used instead of8-acetyl-12-hydroxyheptadecanoic acid. The product is obtained as ayellowish viscous oil.

Anal. Calcd. for C₁₉ H₃₆ O₄ : C, 69.47; H, 11.05; Found: C, 69.54; H,11.69.

EXAMPLE 44 Preparation of8-(1-Hydroxyethyl)-12-hydroxy-12-methylheptadecanoic Acid

This compound is prepared by the method described in Example 9 exceptthat 8-acetyl-12-hydroxy-12-methylheptadecanoic acid is used instead of8-acetyl-12-hydroxyheptadecanoic acid. The product is obtained as acolorless, very viscous oil; pmr (CDCl₃)δ 0.90 (3H,t), 2.35 (2H,t, CH₂COO), 3.82 (1H,m, HCO), 5.90 (3H,s, OH and COOH).

Anal. Calcd. for C₂₀ H₄₀ O₄ : C, 69.72; H, 11.70; Found: C, 69.42; H,12.02.

EXAMPLE 45 Capsule Formulation

8-Acetyl-11-(1-hydroxycyclohexyl)undecanoic acid -- 50 gm.

Stearic Acid (U.S.P. triple pressure) -- 125 gm.

Pluronic F-68 -- 7.5 gm.

Corn starch -- 125 gm.

The stearic acid and pluronic are united in a vessel and melted using awater bath at 60°-65° C. The heating is discontinued and the8-acetyl-12-cyclohexyl-12-hydroxydecanoic acid is dispersed into themixture and the corn starch is added with stirring which is continueduntil the mixture cools to ambient temperature. The mixture is reducedto granules by screening and placed in a number 0 hard gelatincontaining 307.5 mg. of total solids and 50 mg. of8-acetyl-11-(1-hydroxycyclohexyl)undecanoic acid per capsule.

EXAMPLE 46 Parenteral Formulation of a Multidose Solution forIntramuscular and Intravenous Use

8-Acetyl-12-hydroxyheptadecanoic acid -- 1 gram

Tris(hydroxymethyl)aminomethane -- q.s. to adjust solution (ReagentGrade Tham) to pH 7.4

Sodium chloride (U.S.P.) -- q.s. to yield isotonic solution

Methylparaben -- 10 mg.

Propylparaben -- 1 mg.

Distilled water (pyrogen-free) -- q.s. to 10 ml.

The 8-acetyl-12-hydroxyheptadecanoic acid suspended in about 6 ml. ofthe water is treated with tris(hydroxymethyl)aminomethane with stirringuntil the pH reaches 7.4. The methylparaben and propylparaben are addedwith stirring and sufficient sodium chloride added to produce anisotonic solution. After water is added to bring the final volume to 10ml., the solution is sterilized by membrane filtration and placed in avial by an aseptic technique. The solution contains the Tham salt of8-acetyl-12-hydroxyheptadecanoic acid equivalent to 100 mg./ml. of thefree acid.

EXAMPLE 47 Preparation of Suppositories

8-(1-Hydroxyethyl)-12-hydroxyheptadecanoic acid -- 200 gm.

Butylated hydroxyanisole -- 82 mg.

Butylated hydroxytoluene -- 82 mg.

Ethylenediamine tetraacetic acid -- 163 mg.

Glycerine, U.S.P. -- 128 gm.

Sodium chloride, microfine -- 52.5 gm.

Polyethylene glycol 6000 -- 128 gm.

Polyethylene glycol 4000 -- 1269 gm.

The polyethylene glycol 4000 and polyethylene glycol 6000 were placed ina vessel surrounded by a water bath at such a temperature required tomaintain the melted contents at 60°-65° C. To the melt is added thebutylated hydroxyanisole and butylated hydroxytoluene with stirring.Then the ethylenediamine tetraacetic acid and microfine sodium chlorideare added to and dispersed in the mixture. The8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid is then added anddispersed into the mixture. Finally, the temperature is lowered to55°-60° C. and the glycerine added and dispersed.

While maintaining the temperature of 55°-60° C. and continuous mixing,the melt is dispersed into plastic suppository cavities of aconventional suppository cold-molding device. The suppositories thusprepared contain a total of 1.7778 gm. of contents of which 200 mg. are8-(1-hydroxyethyl)-12-hydroxyheptadecanoic acid.

What is claimed is:
 1. The compound having the following formula:##STR51## wherein R is carboxy, a carboxy salt, or derivatized carboxyhaving the formula --COOY wherein Y is alkyl having 1-10 carbon atoms,1-succinimidoethyl, 1-(pivaloyloxy)ethyl, 2-acetamidoethyl, ordiloweralkylamino-loweralkyl;A is oxymethylene; R¹ is formyl, acetyl,propionyl, acryloyl, hydroxyacetyl, 3-hydroxypropionyl, hydroxymethyl,1-hydroxyethyl, 1,2-dihydroxyethyl, 1,3-dihydroxypropyl, or1-hydroxy-1-methylethyl; Z is methylene, ethylene, trimethylene,tetramethylene, vinylene, or ethynylene; R² is independently hydrogen ormethyl; R³ is hydrogen; R⁴ is selected independently from the groupconsisting of hydrogen and methyl; and R⁵ is selected from the groupconsisting of hydrogen, lower alkyl of 1-4 carbon atoms either straightor branched (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl),vinyl, and 2,2,2-trifluoroethyl.
 2. The compound of claim 1 wherein R iscarboxy or a pharmaceutically acceptable carboxy salt.
 3. The compoundof claim 2 which has the formula: ##STR52## wherein R¹ is formyl,acetyl, propionyl, hydroxyacetyl, 1-hydroxyethyl, hydroxymethyl, or1-hydroxy-1-methylethyl; A is oxymethylene; Z is methylene, ethylene,trimethylene, or tetramethylene; R⁴ is hydrogen or methyl; and R⁵ ishydrogen, loweralkyl, vinyl, or 2,2,2-trifluoroethyl.
 4. The compound ofclaim 3 wherein A is oxymethylene, and R⁴ is hydrogen.
 5. The compoundof claim 4 wherein R¹ is acetyl or propionyl.
 6. The compound of claim 5wherein R⁵ is straight chain loweralkyl having 2-5 carbon atoms.
 7. Thecompound of claim 2 which has the formula: ##STR53## wherein A isoxymethylene; R¹ is acetyl or 1-hydroxyethyl; and R⁵ is hydrogen,loweralkyl of 1-4 carbon atoms, or 2,2,2-trifluoroethyl.
 8. The compoundof claim 2 which has the formula: ##STR54## wherein R¹ is formyl,acetyl, propionyl, hydroxymethyl, 1-hydroxy-1-methylethyl,1-hydroxyethyl, or hydroxyacetyl; A is oxymethylene; Z is methylene,ethylene, trimethylene, tetramethylene, or vinylene; and R⁵ is hydrogen,loweralkyl of 1-4 carbon atoms, or 2,2,2-trifluoroethyl.
 9. The compoundof claim 2 which has the formula: ##STR55## wherein R¹ is acetyl,propionyl, 3-hydroxypropionyl, acryloyl, formyl; A is oxymethylene; andR⁵ is hydrogen, loweralkyl, vinyl, or 2,2,2-trifluoroethyl. 10.(5-Acetyl-9-hydroxytetradecyloxy)acetic acid, the compound of claim 9wherein A is oxymethylene, and R¹ is acetyl and R⁵ is ethyl.
 11. Thecompound of claim 2 which has the formula: ##STR56## wherein R¹ ishydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl,1,2-dihydroxyethyl, or 1,3-dihydroxypropyl; A is oxymethylene; Z ismethylene, ethylene, trimethylene, tetramethylene, vinylene, orethynylene; R² and R⁴ are selected independently from a group consistingof hydrogen and methyl; and R⁵ is hydrogen, loweralkyl, vinyl, or2,2,2-trifluoroethyl.
 12. The compound of claim 1 which has the formula:##STR57## wherein A is oxymethylene; R¹ is acetyl, propionyl,hydroxymethyl, or 1-hydroxyethyl; R² is methyl or hydrogen;R⁴ isselected independently from the group consisting of hydrogen and methyl;R⁵ is selected from the group consisting of hydrogen, lower alkyl of 1-4carbon atoms either straight or branched (e.g., methyl, ethyl, propyl,isopropyl, butyl, tert-butyl) vinyl, and 2,2,2-trifluoroethyl; and Y isalkyl having 1-10 carbon atoms, 1-succinimidoethyl, 1-(pivaloylethyl),2-acetamidoethyl, or diloweralkylamino-loweralkyl.
 13. A compositioncomprising the compound of claim 1 in a non-toxic,pharmaceutically-acceptable carrier.
 14. The composition of claim 13which is suitable for oral administration in tablet form.
 15. Thecomposition of claim 13 which is suitable for oral administration incapsule form.
 16. The composition of claim 13 which is suitable forparenteral administration.
 17. The composition of claim 13 which issuitable for use in suppository form.
 18. The compound of claim 1wherein R¹ is formyl, acetyl, propionyl, acryloyl, hydroxy, acetyl, or3-hydroxypropionyl.